Background
In glioblastoma (GBM), promoter methylation of the DNA repair gene O‐methylguanine‐DNA methyltransferase (MGMT) is associated with beneficial chemotherapy.
Purpose/Hypothesis
To analyze ...radiomics features for utilizing the full potential of medical imaging as biomarkers of MGMT promoter methylation.
Study Type
Retrospective.
Population/Subjects
In all, 98 GBM patients with known MGMT (48 methylated and 50 unmethylated tumors).
Field Strength/Sequence
3.0T magnetic resonance (MR) images, containing T1‐weighted image (T1WI), T2‐weighted image (T2WI), and enhanced T1WI.
Assessment
A region of interest (ROI) of the tumor was delineated. A total of 1665 radiomics features were extracted and quantized, and were reduced using least absolute shrinkage and selection operator (LASSO) regularization.
Statistical Testing
After the support vector machine construction, accuracy, sensitivity, and specificity were computed for different sequences. An independent validation cohort containing 20 GBM patients was utilized to further evaluate the radiomics model performance.
Results
Radiomics features of T1WI reached an accuracy of 67.54%. Enhanced T1WI features reached an accuracy of 82.01%, while T2WI reached an accuracy of 69.25%. The best classification system for predicting MGMT promoter methylation status originated from the combination of 36 T1WI, T2WI, and enhanced T1WI images features, with an accuracy of 86.59%. Further validation on the independent cohort of 20 patients produced similar results, with an accuracy of 80%.
Data Conclusion
Our results provide further evidence that radiomics MR features could predict MGMT methylation status in preoperative GBM. Multiple imaging modalities together can yield putative noninvasive biomarkers for the identification of MGMT.
Level of Evidence: 4
Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1380–1387.
Tumor cells adapt to excessive oxidative stress by actuating reactive oxygen species (ROS)‐defensing system, leading to a resistance to oxidation therapy. In this work, self‐delivery photodynamic ...synergists (designated as PhotoSyn) are developed for oxidative damage amplified tumor therapy. Specifically, PhotoSyn are fabricated by the self‐assembly of chlorine e6 (Ce6) and TH588 through π–π stacking and hydrophobic interactions. Without additional carriers, nanoscale PhotoSyn possess an extremely high drug loading rate (up to 100%) and they are found to be fairly stable in aqueous phase with a uniform size distribution. Intravenously injected PhotoSyn prefer to accumulate at tumor sites for effective cellular uptake. More importantly, TH588‐mediated MTH1 inhibition could destroy the ROS‐defensing system of tumor cells by preventing the elimination of 8‐oxo‐2′‐deoxyguanosine triphosphate (8‐oxo‐dG), thereby exacerbating the oxidative DNA damage induced by the photodynamic therapy (PDT) of Ce6 under light irradiation. As a consequence, PhotoSyn exhibit enhanced photo toxicity and a significant antitumor effect. This amplified oxidative damage strategy improves the PDT efficiency with a reduced side effect by increasing the lethality of ROS without generating superabundant ROS, which would provide a new insight for developing self‐delivery nanoplatforms in photodynamic tumor therapy in clinic.
Carrier free photodynamic synergists are developed for oxidative damage amplified tumor therapy by destroying the reactive oxygen species (ROS)‐defensing system without generating excessive ROS, which shed light on the development of self‐delivery nanoplatforms for efficient photodynamic therapy by utilizing the limited oxygen in hypoxic tumors.
Multimodal neuroimaging features provide opportunities for accurate classification and personalized treatment options in the psychiatric domain. This study aimed to investigate whether brain features ...predict responses to the overall treatment of schizophrenia at the end of the first or a single hospitalization. Structural and functional magnetic resonance imaging (MRI) data from two independent samples (N = 85 and 63, separately) of schizophrenia patients at baseline were included. After treatment, patients were classified as responders and non‐responders. Radiomics features of gray matter morphology and functional connectivity were extracted using Least Absolute Shrinkage and Selection Operator. Support vector machine was used to explore the predictive performance. Prediction models were based on structural features (cortical thickness, surface area, gray matter regional volume, mean curvature, metric distortion, and sulcal depth), functional features (functional connectivity), and combined features. There were 12 features after dimensionality reduction. The structural features involved the right precuneus, cuneus, and inferior parietal lobule. The functional features predominately included inter‐hemispheric connectivity. We observed a prediction accuracy of 80.38% (sensitivity: 87.28%; specificity 82.47%) for the model using functional features, and 69.68% (sensitivity: 83.96%; specificity: 72.41%) for the one using structural features. Our model combining both structural and functional features achieved a higher accuracy of 85.03%, with 92.04% responder and 80.23% non‐responders to the overall treatment to be correctly predicted. These results highlight the power of structural and functional MRI‐derived radiomics features to predict early response to treatment in schizophrenia. Prediction models of the very early treatment response in schizophrenia could augment effective therapeutic strategies.
By radiomics strategy, we established prediction models based on structural features and functional features extracted from multi‐modal magnetic resonance imaging (MRI) data of 148 schizophrenia patients collected from two independent samples. The model combining both structural and functional features achieved a prediction accuracy of 85.03% to the overall treatment response. Our results highlight the capability of structural and functional MRI‐derived radiomics features to predict early responses to the treatment in schizophrenia.
Abnormal tumor metabolism causes the hypoxic microenvironment, which greatly limits the efficacy of photodynamic therapy (PDT). In this work, a strategy of metabolic reprogramming is proposed to ...economize O2 for enhanced PDT against hypoxic tumors. The carrier‐free O2‐economizer (designated as LonCe) is prepared based on the metabolic antitumor drug of Lonidamine (Lon) and the photosensitizer of chlorin e6 (Ce6). By virtue of intermolecular interactions, Lon and Ce6 self‐assemble into nanosized LonCe with favorable stability and high drug contents. Compared with Ce6, LonCe exhibits an improved cellular uptake and photodynamic property for tumor treatment. Moreover, LonCe is capable of inhibiting cell metabolism and mitochondrial respiration to remit the tumor hypoxia, which would promote reactive oxygen species (ROS) production and elevate the PDT efficacy on tumor suppression. In vivo experiments indicate that intravenously injected LonCe prefers to accumulate at the tumor site for highly efficient PDT regardless of the hypoxic environment. Besides, the self‐delivery LonCe is fabricated without any carriers, which avoids the excipients induced system toxicity and immunogenicity in vivo. This carrier‐free nanomedicine with cell respiratory inhibition mechanism would expedite the development and clinical translation of photodynamic nanoplatforms in tumor treatment.
A carrier‐free O2‐economizer (designated as LonCe) is developed based on the metabolic drug Lonidamine (Lon) and photosensitizer chlorin e6 (Ce6), which can interrupt cell metabolism and depress mitochondrial respiration to remit the tumor hypoxia. Experiments show that LonCe will greatly improve the antitumor effect by O2‐economized photodynamic therapy regardless of the hypoxic microenvironment.
MicroRNAs are small and non-coding RNA molecules with the master role in regulation of gene expression at post-transcriptional/translational levels. Many methods have been developed for microRNA ...loss-of-function study, such as antisense inhibitors and sponges; however, the robustness, specificity, and stability of these traditional strategies are not highly satisfied. CRISPR/cas9 system is emerging as a novel genome editing tool in biology/medicine research, but its indication in microRNA research has not been studied exclusively. In this study, we clone CRISPR/cas9 constructs with single-guide RNAs specifically targeting biogenesis processing sites of selected microRNAs; and we find that CRISPR/cas9 can robustly and specifically reduce the expression of these microRNAs up to 96%. CRISPR/cas9 also shows an exclusive benefit in control of crossing off-target effect on microRNAs in the same family or with highly conserved sequences. More significantly, for the first time, we demonstrate the long term stability of microRNA knockdown phenotype by CRISPR/cas9 in both in vitro and in vivo models.
Self-delivery of photosensitizer and immune modulator to tumor site is highly recommendable to improve the photodynamic immunotherapy yet remains challenging. Herein, self-delivery photoimmune ...stimulators (designated as iPSs) are developed for photodynamic sensitized tumor immunotherapy. Carrier-free iPSs are constructed by optimizing the noncovalent interactions between the pure drugs of chlorine e6 (Ce6) and NLG919, which avoid the excipients-raised toxicity and immunogenicity. Intravenously administrated iPSs prefer to passively accumulate on tumor tissues for a robust photodynamic therapy (PDT) with the induction of immunogenetic cell death (ICD) cascade to activate cytotoxic T lymphocytes (CTLs) and initiate antitumor immune response. Meanwhile, the concomitant delivery of NLG919 inhibits the activation of indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse the immunosuppressive tumor microenvironment. Ultimately, the photodynamic sensitized immunotherapy with iPSs efficiently inhibit the primary and distant tumor growth with a low system toxicity, which would shed light on the development of self-delivery nanomedicine for clinical transformation in tumor precision therapy.
Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous ...system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.
Attempts to determine why some patients respond to electroconvulsive therapy (ECT) are valuable in schizophrenia. Schizophrenia is associated with aberrant dynamic functional architecture, which ...might impact the efficacy of ECT. We aimed to explore the relationship between pre‐treatment temporal variability and ECT acute efficacy. Forty‐eight patients with schizophrenia and 30 healthy controls underwent functional magnetic resonance imaging to examine whether patterns of temporary variability of functional architecture differ between high responders (HR) and low responders (LR) at baseline. Compared with LR, HR exhibited significantly abnormal temporal variability in right inferior front gyrus (IFGtriang.R), left temporal pole (TPOsup.L) and right middle temporal gyrus (MTG.R). In the pooled patient group, ∆PANSS was correlated with the temporal variability of these regions. Patients with schizophrenia with a distinct dynamic functional architecture appear to reveal differential response to ECT. Our findings provide not only an understanding of the neural functional architecture patterns that are found in schizophrenia but also the possibility of using these measures as moderators for ECT selection.
Compared with low responders, high responders exhibited significantly abnormal temporal variability in right inferior front gyrus, left temporal pole and right middle temporal gyrus. Patients with schizophrenia with a distinct dynamic functional architecture appear to reveal differential response to electroconvulsive therapy.
•PCNSL demonstrated lower rCBF, higher Ktrans and Ve compared with HGG and metastasis.•Both Ktrans and rCBF had good diagnostic performance for discriminating PCNSL.•The combination of rCBF and ...Ktrans has the best diagnostic ability for PCNSL.
Conventional magnetic resonance imaging (MRI) is sometimes difficult to distinguish primary central nervous system lymphoma (PCNSL) from other malignant brain tumors effectively. The study aimed to evaluate the diagnostic performance of arterial spin labeling (ASL) and dynamic contrast-enhanced (DCE)-derived permeability parameters to differentiate PCNSL from high-grade glioma (HGG) and brain metastasis.
Eight patients with PCNSL, twenty one patients with HGG and six brain metastasis underwent preoperative 3.0-T MR imaging including conventional, ASL and DCE. Quantitative parameters including relative cerebral blood flow (rCBF), extravascular extracellular volume fraction (Ve) and the volume transfer constant (Ktrans) among PCNSL, HGG and metastasis were compared with a one-way analysis of variance. In addition, the area under the receiver-operating characteristic (ROC) curve (AUC) was constructed to evaluate the differentiation diagnostic performance of each parameter and the combination.
The PCNSL demonstrated significantly lower rCBF, higher Ktrans and Ve compared with HGG and metastasis. For the ROC analyses, both Ktrans and rCBF had good diagnostic performance for discriminating PCNSL from HGG and metastasis, with the AUC of 0.880 and 0.889. With the combination of rCBF and Ktrans, the diagnostic ability for PCNSL was improved with AUC of 0.986.
rCBF and Ktrans are useful parameters for differentiating PCNSL from HGG and brain metastasis. The combination of rCBF and Ktrans further helps to improve the diagnostic performance of PCNSL.
Abstract
Specific biomarker reflecting neurobiological substrates of schizophrenia (SZ) is required for its diagnosis and treatment selection of SZ. Evidence from neuroimaging has implicated ...disrupted functional connectivity in the pathophysiology. We aimed to develop and validate a method of disease definition for SZ by resting-state functional connectivity using radiomics strategy. This study included 2 data sets collected with different scanners. A total of 108 first-episode SZ patients and 121 healthy controls (HCs) participated in the current study, among which 80% patients and HCs (n = 183) and 20% (n = 46) were selected for training and testing in intra-data set validation and 1 of the 2 data sets was selected for training and the other for testing in inter-data set validation, respectively. Functional connectivity was calculated for both groups, features were selected by Least Absolute Shrinkage and Selection Operator (LASSO) method, and the clinical utility of its features and the generalizability of effects across samples were assessed using machine learning by training and validating multivariate classifiers in the independent samples. We found that the accuracy of intra-data set training was 87.09% for diagnosing SZ patients by applying functional connectivity features, with a validation in the independent replication data set (accuracy = 82.61%). The inter-data set validation further confirmed the disease definition by functional connectivity features (accuracy = 83.15% for training and 80.07% for testing). Our findings demonstrate a valid radiomics approach by functional connectivity to diagnose SZ, which is helpful to facilitate objective SZ individualized diagnosis using quantitative and specific functional connectivity biomarker.
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