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•We identified 8 MVI preoperative risk factors in HCC, including radiomic features.•Radiomic features do not provide significant added value to radiologist scores.•A model integrating ...clinic-radiologic and radiomic features demonstrates good performance for predicting MVI.
Microvascular invasion (MVI) impairs surgical outcomes in patients with hepatocellular carcinoma (HCC). As there is no single highly reliable factor to preoperatively predict MVI, we developed a computational approach integrating large-scale clinical and imaging modalities, especially radiomic features from contrast-enhanced CT, to predict MVI and clinical outcomes in patients with HCC.
In total, 495 surgically resected patients were retrospectively included. MVI-related radiomic scores (R-scores) were built from 7,260 radiomic features in 6 target volumes. Six R-scores, 15 clinical factors, and 12 radiographic scores were integrated into a predictive model, the radiographic-radiomic (RR) model, with multivariate logistic regression.
Radiomics related to tumor size and intratumoral heterogeneity were the top-ranked MVI predicting features. The related R-scores showed significant differences according to MVI status (p <0.001). Regression analysis identified 8 MVI risk factors, including 5 radiographic features and an R-score. The R-score (odds ratio OR 2.34) was less important than tumor capsule (OR 5.12), tumor margin (OR4.20), and peritumoral enhancement (OR 3.03). The RR model using these predictors achieved an area under the curve (AUC) of 0.909 in training/validation and 0.889 in the test set. Progression-free survival (PFS) and overall survival (OS) were significantly different between the RR-predicted MVI-absent and MVI-present groups (median PFS: 49.5 vs. 12.9 months; median OS: 76.3 vs. 47.3 months). RR-computed MVI probability, histologic MVI, tumor size, and Edmondson-Steiner grade were independently associated with disease-specific recurrence and mortality.
The computational approach, integrating large-scale clinico-radiologic and radiomic features, demonstrates good performance for predicting MVI and clinical outcomes. However, radiomics with current CT imaging analysis protocols do not provide statistically significant added value to radiographic scores.
The most effective treatment for hepatocellular carcinoma (HCC) is surgical removal of the tumor but often recurrence occurs, partly due to the presence of microvascular invasion (MVI). Lacking a single highly reliable factor able to preoperatively predict MVI, we developed a computational approach to predict MVI and the long-term clinical outcome of patients with HCC. In particular, the added value of radiomics, a newly emerging form of radiography, was comprehensively investigated. This computational method can enhance the communication with the patient about the likely success of the treatment and guide clinical management, with the aim of finding drugs that reduce the risk of recurrence.
Objectives
This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its ...prognostic value.
Methods
For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients.
Results
The radiomics signature comprised eight LN-status–related features and showed significant association with LN metastasis in both cohorts (
p
< 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both
p
< 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival.
Conclusions
Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making.
Key Points
• The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup.
• Prognosis of high-risk patients remains dismal after curative-intent resection.
• The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.
Low-density compressible materials enable various applications but are often hindered by structure-derived fatigue failure, weak elasticity with slow recovery speed and large energy dissipation. Here ...we demonstrate a carbon material with microstructure-derived super-elasticity and high fatigue resistance achieved by designing a hierarchical lamellar architecture composed of thousands of microscale arches that serve as elastic units. The obtained monolithic carbon material can rebound a steel ball in spring-like fashion with fast recovery speed (∼580 mm s
), and demonstrates complete recovery and small energy dissipation (∼0.2) in each compress-release cycle, even under 90% strain. Particularly, the material can maintain structural integrity after more than 10
cycles at 20% strain and 2.5 × 10
cycles at 50% strain. This structural material, although constructed using an intrinsically brittle carbon constituent, is simultaneously super-elastic, highly compressible and fatigue resistant to a degree even greater than that of previously reported compressible foams mainly made from more robust constituents.
Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate ...a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel‐catalyzed hydromonofluoroalkylation of unactivated alkenes and copper‐catalyzed C−C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro‐alkoxy, ‐alkylamino motifs with commercially available heteroatom‐based coupling partners.
A general method allows preparation of diverse monofluorides based on the monofluoroalkyl triflate scaffold. Both nickel‐catalyzed hydromonofluoroalkylation of unactivated alkenes and copper‐catalyzed monofluoroalkylation of Grignard reagents were studied. Further utilities including conversion into conventional fluoroalkylating reagents and construction of monofluoro‐alkoxy, ‐alkylamino motifs.
Inflammation is implicated in epileptogenesis. Activated microglia and macrophages (MG/MΦ) are found in the brains of patients with epilepsy-related diseases and animal models of epilepsy. It is not ...yet known how the MG/MΦ activation phenotype affects pathological changes in the brain after a single seizure. In this study, we had 2 main purposes: first, to characterize post-status epilepticus (SE) inflammation by tracking MG/MΦ polarization, and, second, to explore the role of an innate immune receptor adaptor protein, namely, myeloid differentiation primary response gene 88 (MyD88), in the induction of SE in a mouse model. A lithium–pilocarpine model of seizure conditions was generated in C57BL/6 mice. The intensity and distribution of MG/MΦ polarization were tracked by fluorescent immunohistochemistry and Western blotting for the polarization markers inducible nitrogen oxygenized synthase, arginase-1, CD163, and mannose receptor. We observed steadily increasing M1 MG/MΦ along with MyD88 signal upregulation after SE in the hippocampi of mice, whereas the M2 marker arginase-1 was localized mainly in astrocytes rather than in MG/MΦ. Inhibition or gene knockout of MyD88 reduced M1 MG/MΦ and gliosis although increasing M2 MG/MΦ in the hippocampi of SE mice. MyD88 inhibition also augmented glutamate transporter 1 expression and reduced N-methyl-D-aspartate receptor NR1 subunit expression in the hippocampus to protect pyramidal neurons from apoptosis. These data suggest that MG/MΦ polarization after SE impacts the pathological outcome of the hippocampus via MyD88 signaling and point to MyD88 as a potential neuroprotective target for epilepsy therapy.
Due to the intelligent survival strategy and self-preservation of methicillin-resistant Staphylococcus aureus (MRSA), many antibiotics are ineffective in treating MRSA infections. Nano-drug delivery ...systems have emerged as a new method to overcome this barrier. The aim of this study was to construct a novel nano-drug delivery system for the treatment of MRSA infection, and to evaluate the therapeutic effect and biotoxicity of this system. We prepared a nano silver metal-organic framework using 2-methylimidazole as ligand and silver nitrate as ion provider. Vancomycin (Vanc) was loaded with Ag-MOF, and nano-sized platelet vesicles were prepared to encapsulate Ag-MOF-Vanc, thus forming the novel platelet membrane-camouflaged nanoparticles PLT@Ag-MOF-Vanc.
The synthesized Ag-MOF particles had uniform size and shape of radiating corona. The mean nanoparticle size and zeta potential of PLT@Ag-MOF-Vanc were 148 nm and - 25.6 mV, respectively. The encapsulation efficiency (EE) and loading efficiency (LE) of vancomycin were 81.0 and 64.7 %, respectively. PLT@Ag-MOF-Vanc was shown to be a pH-responsive nano-drug delivery system with good biocompatibility. Ag-MOF had a good inhibitory effect on the growth of three common clinical strains (Escherichia coli, Pseudomonas aeruginosa, and S. aureus). PLT@Ag-MOF-Vanc showed better antibacterial activity against common clinical strains in vitro than free vancomycin. PLT@Ag-MOF-Vanc killed MRSA through multiple approaches, including interfering with the metabolism of bacteria, catalyzing reactive oxygen species production, destroying the integrity of cell membrane, and inhibiting biofilm formation. Due to the encapsulation of the platelet membrane, PLT@Ag-MOF-Vanc can bind to the surface of the MRSA bacteria and the sites of MRSA infection. PLT@Ag-MOF-Vanc had a good anti-infective effect in mouse MRSA pneumonia model, which was significantly superior to free vancomycin, and has no obvious toxicity.
PLT@Ag-MOF-Vanc is a novel effective targeted drug delivery system, which is expected to be used safely in anti-infective therapy of MRSA.
Background
Microvascular invasion (MVI) is implicated in the poor prognosis of hepatocellular carcinoma (HCC). Presurgical stratifying schemes have been proposed for HCC‐MVI but lack external ...validation.
Purpose
To perform external validation and comparison of four presurgical stratifying schemes for the prediction of MVI using gadoxetic acid‐based MRI in a cohort of HCC patients.
Study Type
Retrospective.
Subjects
Included were 183 surgically resected HCCs from patients who underwent pretreatment MRI.
Field Strength/Sequence
This includes 1.5–3.0 T with T2, T1, diffusion‐weighted imaging (DWI), and dynamic gadoxetic acid contrast‐enhancement imaging sequences.
Assessment
A two‐trait predictor of venous invasion (TTPVI), Lei model, Lee model, and Xu model were compared. We relied on preoperative characteristics and imaging findings via four independent radiologists who were blinded to histologic results, as required by the tested tools.
Statistical Test
Tests of accuracy between predicted and observed HCC‐MVI rates using receiver operating characteristic (ROC) curve and decision curve analysis. The intraclass correlation coefficient (ICC) and Cronbach's alpha statistics were used to evaluate reproducibility.
Results
HCC‐MVI was identified in 52 patients (28.4%). The average ROC curves (AUCs) for HCC‐MVI predictions were 0.709–0.880, 0.714–0.828, and 0.588–0.750 for the Xu model, Lei model, and Lee model, respectively. The rates of accuracy were 60.7–81.4%, 69.9–75.9%, and 65.6–73.8%, respectively. Decision curve analyses indicated a higher benefit for the Xu and Lei models compared to the Lee model. The ICC and Cronbach's alpha index were highest in the Lei model (0.896/0.943), followed by the Xu model (0.882/0.804), and the Lee model (0.769/0.715). The TTPVI resulted in a Cronbach's alpha index of 0.606 with a sensitivity of 34.6–61.5% and a specificity of 76.3–91.6%.
Data Conclusion
Stratifying schemes relying on gadoxetic acid‐enhanced MRI provide an additional insight into the presence of preoperative MVI. The Xu model outperformed the other models in terms of accuracy when performed by an experienced radiologist. Conversely, the Lei model outperformed the other models in terms of reproducibility.
Level of Evidence
3
Technical Efficacy Stage
2 J. Magn. Reson. Imaging 2020;52:433–447.
Rational
Minocycline is a second-generation, semi-synthetic tetracycline, and has broad spectrum-antibacterial activity. Interestingly, many studies have demonstrated that minocycline is beneficial ...for depression, which may be due to its effects on neuroinflammation modulation. Recently, gut microbiota imbalance has been found in depression patient and animal models.
Objectives
Based on the fact of minocycline usually acting as an antibiotic and the relationship between depression, gut microbiota, and neuroinflammation, we designed this study to detect the effects of chronic minocycline treatment on antidepression, neuroinflammation, and gut microbiota modulation.
Results
Our results showed that minocycline treatment for 4 weeks, not acute treatment, exerted antidepressant effect in mice exposed to unpredictable chronic mild stress (CUMS). Further results suggested that chronic minocycline treatment inhibited neuroinflammation of hippocampus and altered species abundance and metabolites of gut microbiota. Meantime, we found that chronic minocycline treatment ameliorated intestinal barrier disruption and reduced the bacteriological indexes, such as diamine oxidase, C-reaction protein, and endotoxin in peripheral blood of CUMS mice.
Conclusions
To sum up, our findings confirm that chronic minocycline treatment exerts the antidepressant effect, inhibits neuroinflammation, and modulates gut microbiota. All of these imply that the antidepressant mechanism of chronic minocycline treatment is maybe due to the combined action of neuroinflammation and gut microbiota modulation, which need further prospective studies.
Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of ...neonatal sevoflurane exposure on cell‐type‐specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single‐nucleus RNA sequencing (snRNA‐seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single‐cell trajectory analysis, and genome‐wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re‐defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease‐relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA‐seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
To describe cellular heterogeneity, uncover markers for each cell type, and reveal differentially regulated genes in the mouse prefrontal cortex after multiple sevoflurane exposures by using single‐nucleus RNA sequencing.
The androgen receptor (AR) pathway is critical for prostate cancer carcinogenesis and development; however, after 18‐24 months of AR blocking therapy, patients invariably progress to ...castration‐resistant prostate cancer (CRPC), which remains an urgent problem to be solved. Therefore, finding key molecules that interact with AR as novel strategies to treat prostate cancer and even CRPC is desperately needed. In the current study, we focused on the regulation of RNA‐binding proteins (RBPs) associated with AR and determined that the mRNA and protein levels of AR were highly correlated with Musashi2 (MSI2) levels. MSI2 was upregulated in prostate cancer specimens and significantly correlated with advanced tumor grades. Downregulation of MSI2 in both androgen sensitive and insensitive prostate cancer cells inhibited tumor formation in vivo and decreased cell growth in vitro, which could be reversed by AR overexpression. Mechanistically, MSI2 directly bound to the 3′‐untranslated region (UTR) of AR mRNA to increase its stability and, thus, enhanced its transcriptional activity. Our findings illustrate a previously unknown regulatory mechanism in prostate cancer cell proliferation regulated by the MSI2‐AR axis and provide novel evidence towards a strategy against prostate cancer.
This is the first description of a role for the RNA‐binding protein MSI2 in regulating AR stability in prostate cancer. MSI2 upregulates AR mRNA stability through directly binding with 3′‐UTR of AR mRNA, which indicates that targeting MSI2 may be a novel and unique anti–androgen therapy for prostate cancer.
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