| 1. |
- Xie, Yuan, et al.
(författare)
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Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma
- 2023
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 25:6, s. 1073-1084
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.Methods: Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms.Results: We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.Conclusions: These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
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| 2. |
- Xie, Yuan, et al.
(författare)
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Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing
- 2021
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Ingår i: JCI Insight. - : American Society For Clinical Investigation. - 2379-3708. ; 6:15
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Tidskriftsartikel (refereegranskat)abstract
- Passage of systemically delivered pharmacological agents into the brain is largely blocked by the blood-brain-barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). Tumor vessels in glioblastoma (GBM), the most common malignant brain tumor in humans, are abnormally permeable, but this phenotype is heterogeneous and may differ between the tumor's center and invasive front. Here, through single-cell RNA sequencing (scRNA-seq) of freshly isolated ECs from human glioblastoma and paired tumor peripheral tissues, we have constructed a molecular atlas of human brain ECs providing unprecedented molecular insight into the heterogeneity of the human BBB and its molecular alteration in glioblastoma. We identified 5 distinct EC phenotypes representing different states of EC activation and BBB impairment, and associated with different anatomical locations within and around the tumor. This unique data resource provides key information for designing rational therapeutic regimens and optimizing drug delivery.
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| 3. |
- Yang, Fan, et al.
(författare)
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Uncovering a Distinct Gene Signature in Endothelial Cells Associated With Contrast Enhancement in Glioblastoma
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Glioblastoma (GBM) is the most aggressive and lethal type of brain tumors. Magnetic resonance imaging (MRI) has been commonly used for GBM diagnosis. Contrast enhancement (CE) on T1-weighted sequences are presented in nearly all GBM as a result of high vascular permeability in glioblastomas. Although several radiomics studies indicated that CE is associated with distinct molecular signatures in tumors, the effects of vascular endothelial cells, the key component of blood brain barrier (BBB) controlling vascular permeability, on CE have not been thoroughly analyzed. Methods Endothelial cell enriched genes have been identified using transcriptome data from 128 patients by a systematic method based on correlation analysis. Distinct endothelial cell enriched genes associated with CE were identified by analyzing difference of correlation score between CE-high and CE-low GBM cases. Immunohistochemical staining was performed on in-house patient cohort to validate the selected genes associated with CE. Moreover, a survival analysis was conducted to uncover the relation between CE and patient survival. Results We illustrated that CE is associated with distinct vascular molecular imprints characterized by up-regulation of pro-inflammatory genes and deregulation of BBB related genes. Among them, PLVAP is up-regulated, whereas TJP1 and ABCG2 are down-regulated in the vasculature of GBM with high CE. In addition, we found that the high CE is associated with poor prognosis and GBM mesenchymal subtype. Conclusion We provide an additional insight to reveal the molecular trait for CE in MRI images with special focus on vascular endothelial cells, linking CE with BBB disruption in the molecular level. This study provides a potential new direction that may be applied for the treatment optimization based on MRI features.
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| 4. |
- Ren, Liqun, et al.
(författare)
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Heterogenic Distribution of Aromatic L-Amino Acid Decarboxylase Neurons in the Rat Spinal Cord
- 2017
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Ingår i: Frontiers in Integrative Neuroscience. - : Frontiers Media SA. - 1662-5145. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aromatic L-amino acid decarboxylase (AADC) is an essential enzyme in the synthesis of serotonin, dopamine, and certain trace amines and is present in a variety of organs including the brain and spinal cord. It is previously reported that in mammalian spinal cord AADC cells (called D-cells) were largely confined to a region around the central canal and that they do not produce monoamines. To date, there has not been a detailed description of their distribution and morphology in mammals. In the present study this issue is systematically investigated using immunohistochemistry. We have found that AADC cells in the rat spinal cord are both more numerous and more widely distributed than previously reported. In the gray matter, AADC neurons immunolabeled for NeuN were not only found in the region around the central canal but also in the dorsal horn, intermediate zone, and ventral horn. In the white matter a large number of glial cells were AADC-immunopositive in different spinal segments and the vast majority of these cells expressed oligodendrocyte and radial glial phenotypes. Additionally, a small number of AADC neurons labeled for NeuN were found in the white matter along the ventral median fissure. The shapes and sizes of AADC neurons varied according to their location. For example, throughout cervical and lumbar segments AADC neurons in the intermediate zone and ventral horn tended to be rather large and weakly immunolabeled, whereas those in comparable regions of sacrocaudal segments were smaller and more densely immunolabeled. The diverse morphological characteristics of the AADC cells suggests that they could be further divided into several subtypes. These results indicate that AADC cells are heterogeneously distributed in the rat spinal cord and they may exert different functions in different physiological and pathological situations.
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| 5. |
- Zhang, Xing, et al.
(författare)
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Diagnosing NB plasmas on the EAST tokamak with new time-of-flight neutron spectrometer
- 2014
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 54:10, s. 104008-
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Tidskriftsartikel (refereegranskat)abstract
- The new neutron spectrometer time-of-flight enhanced diagnostics (TOFED) for the EAST tokamak is presented and its characteristics are described in terms of simulation results, as well as the interface in the torus hall along with new neutral beam (NB) injectors. The use of TOFED for studies of the slowing down of NB-injected deuterons is illustrated. The implications of measuring the neutron emission on a long pulse machine are discussed together with the experimental challenges and diagnostic possibilities approaching those to be encountered in continuous operation.
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| 6. |
- Zhang, Yanyu, et al.
(författare)
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1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas
- 2021
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Ingår i: Cellular Oncology. - : Springer. - 2211-3428 .- 2211-3436. ; 44:1, s. 193-204
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Tidskriftsartikel (refereegranskat)abstract
- Background Tumor-associated macrophages (TAM)s are critical regulators of glioma progression. As yet, however, TAMs in isocitrate dehydrogenase (IDH) mutated lower-grade gliomas (LGGs) have not been thoroughly investigated. The aim of this study was to determine whether 1p/19q co-deletion status affects the TAM phenotype or its prevalence in IDH mutated LGGs. Methods TAMs in IDH mutated LGGs were analyzed using transcriptome data from 230 samples in the TCGA database in combination with transcriptome data from single-cell RNA sequencing of IDH-mutated LGGs. Proteins potentially involved in TAM regulation were examined by immuno-staining in primary LGG samples harboring IDH mutations. Essential signaling pathways regulating TAM phenotypes were investigated in a glioma mouse model using small molecule inhibitors. Results Most of the TAMs in IDH-mutated LGGs expressed the M1 activation markers CD86 and TNF, whereas a subset of individual TAMs co-expressed both M1 and M2-related markers. Bioinformatics analysis in combination with immuno-staining of IDH-mutated patient samples revealed higher amounts of TAMs expressing M2-related markers in 1p/19q non-codeletion IDH-mutated LGGs compared to 1p/19q codeletion LGGs. The levels of transforming growth factor beta 1 (TGF beta 1) and macrophage colony-stimulating factor (M-CSF) were significantly higher in 1p/19q non-codeletion LGGs than in 1p/19q codeletion LGGs. M-CSF and TGF beta 1 signal inhibition decreased tumor growth and modulated the TAM phenotype in a glioma mouse model. Conclusions Our data indicate that 1p/19q co-deletion status relates to distinct TAM infiltration in gliomas, which is likely mediated by M-CSF and TGF beta 1 signaling. M-CSF and TGF beta 1 signaling may play a pivotal role in regulating the TAM phenotype in glioma.
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| 7. |
- Deng, Xiangyi, et al.
(författare)
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ECO : An Integrated Gene Expression Omnibus for Mouse Endothelial Cells In Vivo
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial cell (EC) plays critical roles in vascular physiological and pathological processes. With the development of high-throughput technologies, transcriptomics analysis of EC has increased dramatically and a large amount of informative data have been generated. The dynamic patterns of gene expression in ECs under various conditions were revealed. Unfortunately, due to the lack of bioinformatics infrastructures, reuse of these large-scale datasets is challenging for many scientists. Here, by systematic re-analyzing, integrating, and standardizing of 203 RNA sequencing samples from freshly isolated mouse ECs under 71 conditions, we constructed an integrated mouse EC gene expression omnibus (ECO). The ECO database enables one-click retrieval of endothelial expression profiles from different organs under different conditions including disease models, genetic modifications, and clinically relevant treatments in vivo. The EC expression profiles are visualized with user-friendly bar-plots. It also provides a convenient search tool for co-expressed genes. ECO facilitates endothelial research with an integrated tool and resource for transcriptome analysis. The ECO database is freely available at https://heomics. shinyapps.io/ecodb/.
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| 8. |
- Ge, Li, 1974-, et al.
(författare)
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The Investigation and Analysis on Chinese Medicine Constitution Types of Pregnant Metaphase Women in Fuzhou
- 2013
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Ingår i: Chinese General Practice. - Beijing. - 1007-9572. ; 16:6A, s. 1920-1922
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Tidskriftsartikel (refereegranskat)abstract
- 【Abstract】Objective To investigate and analyze the Chinese medicine constitution types of pregnant metaphase women in Fuzhou of China. Methods Cross-sectional study and stratified sampling were used. A scale, , was as a tool for investigation. 1000 scale copies were handed out. 989 scale copies were got after excluding the scale copies with logic error. Constitution types were described by constituent ratio. Results In Fuzhou, the Chinese medicine constitution types of pregnant metaphase women were as following: Yang-deficiency type was 28.5%, damp-heat type was 25.5%, Yin-deficiency type was 25.2%, Qi-depression type and Qi-deficiency type were 23.1% respectively, gentleness type was 20.2%, stasis type was 19.1%, phlegm type was 10.9%, and special intrinsic type was 7.0%. The front three constitution types in different age groups: 20 years old～group: Qi-deficiency type was 29.4%, gentleness type was 24.8%, Yin-deficiency type and yang-deficiency type were 24.2% respectively; 25 years old～group:Yang-deficiency type was 27.6%, Yin-deficiency type and damp-heat type were 23.3% respectively; 30 years old～group: damp-heat type was 34.4%, Yang-deficiency type was 33.9%, Yin-deficiency type was 30.8%. The distribution of constitution types in different education background groups was similar as that of total constitution types of pregnant metaphase women. Conclusions The constitution type’s characteristics of pregnant metaphase women in Fuzhou were inclined to deficiency, heat and damp, and Qi-depression. Guided by the theory of “Preventive Treatment of Disease”, the staff working on antepartum care may provide targeted care according to different body constitution types of pregnant women.
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| 9. |
- Huang, Hua, 1986-, et al.
(författare)
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ELTD1-deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma.
- 2021
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 24:3, s. 398-411
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tumor vessels in glioma are molecularly and functionally abnormal, contributing to treatment resistance. Proteins differentially expressed in glioma vessels can change vessel phenotype and be targeted for therapy. ELTD1 (Adgrl4) is an orphan member of the adhesion G-protein-coupled receptor family upregulated in glioma vessels, and has been suggested as a potential therapeutic target. However, the role of ELTD1 in regulating vessel function in glioblastoma is poorly understood.METHODS: ELTD1 expression in human gliomas and its association with patient survival was determined using tissue microarrays and public databases. The role of ELTD1 in regulating tumor vessel phenotype was analyzed using orthotopic glioma models and ELTD1 -/- mice. Endothelial cells isolated from murine gliomas were transcriptionally profiled to determine differentially expressed genes and pathways. The consequence of ELTD1-deletion on glioma immunity was determined by treating tumor bearing mice with PD-1-blocking antibodies.RESULTS: ELTD1 levels were upregulated in human glioma vessels, increased with tumor malignancy, and were associated with poor patient survival. Progression of orthotopic gliomas was not affected by ELTD1-deletion, however, tumor vascular function was improved in ELTD1 -/- mice. Bioinformatic analysis of differentially expressed genes indicated increased inflammatory response and decreased proliferation in tumor endothelium in ELTD1 -/- mice. Consistent with an enhanced inflammatory response, ELTD1-deletion improved T-cell infiltration in GL261-bearing mice after PD-1 checkpoint blockade.CONCLUSION: Our data demonstrate that ELTD1 participates in inducing vascular dysfunction in glioma, and suggests that targeting of ELTD1 may normalize the vessels and improve the response to immunotherapy.
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| 10. |
- Long, Jianzhan, 1979, et al.
(författare)
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Influences of Cr contents on oxidation behavior of WC-Co-Ni-Cr cemented carbides at 900 °C
- 2024
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Ingår i: International Journal of Refractory Metals and Hard Materials. - 0263-4368 .- 2213-3917. ; 118
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Tidskriftsartikel (refereegranskat)abstract
- Modification of binder composition is an effective way to improve the oxidation resistance of WC-Co-Ni-Cr cemented carbide. Since the adjustment of Ni and Cr contents in the Co-Ni-Cr binder alters the oxidation behavior and oxidation products, WC-Co-Ni-Cr cemented carbide is expected to achieve excellent oxidation resistance in severe service conditions. In this paper, the influences of Cr contents in Co-Ni-Cr binder phase with a fixed total amount of Co and Ni on the oxidation behavior of WC-Co-Ni-Cr cemented carbides at 900 °C was investigated. The oxide morphology and phase distribution were focused. The oxidation mechanism of WC-Co-Ni-Cr cemented carbide was discussed. It has been shown that Co-rich regions are preferentially oxidized in the initial stage of oxidation. As oxidation proceeds (60 min), the dominant oxidation product on the alloy surface is NiO. The oxidation resistance of the WC-Co-Ni-Cr cemented carbide increases with increasing Cr content in the binder. Compared to the series of WC-2Co-11Ni-xCr, WC-6.5Co-6.5Ni-xCr presents a better overall oxidation resistance due to the formation of Cr2O5 in the middle of the oxide layer.
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