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Tumor-associated macrophages: from mechanisms to therapy.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

A complex network of chemokines and their receptors influences the development of primary tumours and metastases. New information about the biological role of chemokines in these processes is providing insights into host–tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Could manipulating the local chemokine network have therapeutic benefits in malignant disease?

Cancer and the chemokine network

https://www.cell.com/trends/neurosciences/pdf/S0166-2236(09)00153-2.pdf

Molecular dissection of reactive astrogliosis and glial scar formation.

Chronic mild stress exacerbates severity of experimental autoimmune encephalomyelitis in association with altered non-coding RNA and metabolic biomarkers.

There is a complex interaction between cancer and the immune system. Tumor-associated macrophages (TAMs) can be subverted by the cancer to adopt a pro-tumor phenotype to aid tumor growth. These anti-inflammatory, pro-tumor TAMs have been shown to contribute to a worsened outcome in several different types of cancer. Various strategies aimed at combating the pro-tumor TAMs have been developed. Several therapies, such as oncolytic viral therapy and high-intensity focused ultrasound, have been shown to stimulate TAMs and suppress tumor growth. Targeting TAMs is a promising way to combat cancer, but sensitive imaging methods that are capable of detecting these therapeutic responses are needed. A promising idea is to use imaging contrast agents to label TAMs to determine their relative number and location within, and around the tumor. This can provide information about the efficacy of TAM depletion therapies, as well as macrophage-stimulating therapies. In this review, we describe various in vivo MRI methods capable of tracking TAMs, and conclude with a short section on tracking TAMs in patients.

https://journals.sagepub.com/doi/pdf/10.1177/1178623X18771974

In Vivo MR Imaging of Tumor-Associated Macrophages: The Next Frontier in Cancer Imaging:

OBJECTIVE Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system. Its pathogenesis remains unknown. Like glioblastomas, AT/RTs contain brain cancer stem cells (CSCs) that suppress the immunity of patients and are resistant to conventional chemotherapy and radiation therapy. Considerable infiltration of immune cells, including macrophages/microglia, dendritic cells and T-cells, has been noted in glioblastomas, which correlates with poor prognosis. The present study examines the significance of infiltrating immune cells in four cases of AT/RT; including one associated with an autoimmune disease, Henoch-Schonlein purpura. METHODS Tumor tissues from four patients with AT/RT were analyzed and compared with those from four patients with glioblastomas. The frequency of immune cells, including CD68+, CD4+, and CD8+ cells, was assessed by scoring for statistical analysis. RESULTS The infiltration of immune cells was identified in the case of AT/RT associated with HSP and three other cases of infratentorial AT/RTs. Moderate infiltration of CD68+ macrophages/microglia and CD4+ cells was noted in AT/RTs with no significant difference from that in glioblastomas (p > 0.05). However, the infiltration of CD8+ T-cells was significantly higher in AT/RTs than that in glioblastomas (p < 0.05); CD4+/CD8+ ratio was significantly lower in AT/RTs than that in glioblastomas (p < 0.05). In addition, eosinophils were found in all AT/RTs, but not in glioblastomas. CONCLUSIONS These findings suggest an immune microenvironment of AT/RTs with more immune effectors than glioblastomas. Our observation contributes to understanding the growth environment of AT/RTs for which adjuvant immunotherapy may be potentially beneficial.

/pdf/immune-cell-infiltrates-in-atypical-teratoid-rhabdoid-tumors-1wjf2sb3q8.pdf

Immune Cell Infiltrates in Atypical Teratoid/Rhabdoid Tumors

Background: Despite the significant role microglia play in the pathology of multiple sclerosis (MS),medications that act within the central nervous system (CNS) to inhibit microglia have not yet been identified as treatmentoptions.Objective: We screened 1040 compounds with the aim of identifying inhibitors of microglia to reduce neuroinflammation.Methods: The NINDs collection of 1040 compounds, where most are therapeutic medications, was tested at 10 µM finalconcentration on lipopolysaccharide (LPS)-activated human microglia. An ELISA was run on the media to measure thelevel of TNF-α as an indicator of microglia activity. For compounds that reduce LPS-activated TNF-α levels by over 50%,considered as a potential inhibitor of interest, toxicity tests were conducted to exclude non-specific cytotoxicity.Promising compounds were subjected to further analyses, including toxicity to other CNS cell types, and multiplex assays.Results: Of 1040 compounds tested, 123 reduced TNF-α levels of LPS-activated microglia by over 50%. However, mostof these were cytotoxic to microglia at the concentration tested while 54 were assessed to be non-toxic. Of the latter,spironolactone was selected for further analyses. Spironolactone reduced TNF-α levels of activated microglia by 50-60%at 10 µM, and this concentration did not kill microglia, neurons or astrocytes. In multiplex assays, spironolactone reducedseveral molecules in activated microglia. Finally, during the screening, we identified 9 compounds that elevated furtherthe TNF-α levels in LPS-activated microglia.Conclusion: Many of the non-toxic compounds identified in this screen as inhibitors of microglia, includingspironolactone, may be explored as viable therapeutic options in MS.

V. Wee Yong

Papers

Chronic mild stress exacerbates severity of experimental autoimmune encephalomyelitis in association with altered non-coding RNA and metabolic biomarkers.

In Vivo MR Imaging of Tumor-Associated Macrophages: The Next Frontier in Cancer Imaging:

Immune Cell Infiltrates in Atypical Teratoid/Rhabdoid Tumors

Screening for inhibitors of microglia to reduce neuroinflammation.

Neuroprotection of minocycline by inhibition of extracellular matrix metalloproteinase inducer expression following intracerebral hemorrhage in mice.