A novel pH ratiometrically responsive surface-enhanced resonance Raman scattering (SERRS) probe was developed for tumor acidic margin delineation and image-guided surgery.
Background
In the setting of drug-resistant epilepsy (DRE), the success of surgery depends on the ability to accurately locate the epileptic foci to be resected or disconnected. However, the epileptic foci in a considerable percentage of the DRE patients cannot be adequately localised. This warrants the need for a reliable imaging strategy to identify the “concealed” epileptic regions.
Methods
Brain specimens from DRE patients and kainate-induced epileptic mouse models were immuno-stained to evaluate the integrity of the blood-brain barrier (BBB). The expression of low-density lipoprotein receptor-related protein-1 (LRP1) in the epileptic region of DRE patients and kainate models was studied by immunofluorescence. A micellar-based LRP1-targeted paramagnetic probe (Gd
3+
-LP) was developed and its ability to define the epileptic foci was investigated by magnetic resonance imaging (MRI).
Findings
The integrity of the BBB in the epileptic region of DRE patients and kainate mouse models were demonstrated. LRP1 expression levels in the epileptic foci of DRE patients and kainate models were 1.70–2.38 and 2.32–3.97 folds higher than in the control brain tissues, respectively.
In vivo
MRI demonstrated that Gd
3+
-LP offered 1.68 times higher (
P
< 0.05) T1-weighted intensity enhancement in the ipsilateral hippocampus of chronic kainite models than the control probe without LRP1 specificity.
Interpretation
The expression of LRP1 is up-regulated in vascular endothelium, activated glia in both DRE patients and kainate models. LRP1-targeted imaging strategy may provide an alternative strategy to define the “concealed” epileptic foci by overcoming the intact BBB.
Funding
This work was supported by the National Natural Science Foundation, Shanghai Science and Technology Committee, Shanghai Municipal Science and Technology, Shanghai Municipal Health and Family Planning Commission and the National Postdoctoral Program for Innovative Talents.
The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1 WT ) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as β-catenin gene, pivotal for Wnt/βcatenin signaling, were upregulated in 206 IDH1 WT glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of β-catenin protein were further verified in IDH1 WT GBM patients and IDH1 WT GL261 glioma allografts. Subsequently, we found that IDH1 WT GL261 cell-derived conditioned medium activated Wnt/βcatenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/β-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1 WT GBM allografts by simultaneously enhancing cytotoxic CD8 + T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1 WT GBM allografts after the blockade of Wnt signaling. Finally, gavage administration of a Wnt signaling inhibitor significantly restrained tumor proliferation and improved the survival of model mice bearing IDH1 WT GBM allografts. Depletion of CD8 + T cells remarkably abrogated the therapeutic efficacy induced by the Wnt signaling inhibitor. Overall, the present work indicates that the crosstalk between IDH1 WT glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/β-catenin signaling is a promising complement for IDH1 WT GBM treatment by improving the hostile immunosuppressive microenvironment.
The joint replenishment and delivery problem with fuzzy chance constraint resource restriction is considered. In the proposed approach, the objective function is to minimize the ordering cost, the inventory holding cost, the transportation cost and the customer waiting cost. Mathematical model is developed, and differential evolution (DE) algorithm is proposed to solve the problem. The performance of the algorithm is then verified and test under the indirect group strategy for 1600 randomly generated problems. The results show the robust performance of the proposed algorithms.
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