COVID-19-associated monocytic encephalitis(CAME):histological and proteomic evidence from autopsy

Severe neurological symptoms are associated with Coronavirus disease 2019(COVID-19).However,the morphologic features,pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection.In this study,neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining,ultrastructural examination under electron microscopy,and an image threshold method,in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals.Differentially expressed proteins were identified by quantitative proteomic assays.Histopathological findings included neurophagocytosis,microglia nodules,satellite phenomena,extensive edema,focal hemorrhage,and infarction,as well as infiltrating mononuclear cells.Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes,severe damage of the blood-brain barrier(BBB)and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+monocytes and occasionally CD4+/CD8+T lymphocytes.Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses,autophagy and cellular metabolism in COVID-19 patient brains compared with control brains.Proteins involved in brain development,neuroprotection,and extracellular matrix proteins of the basement membrane were downregulated,potentially caused by the activation of transforming growth factorβreceptor and vascular endothelial growth factor signaling pathways.Thus,our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis(CAME)and suggest potential therapeutic targets.

Bottlenecks and opportunities in immunotherapy for glioma:a narrative review

Glioma is the most aggressive brain tumor having invasive ability and a highly heterogeneous phenotype.Many patients with glioma respond poorly to traditional surgery or temozolomide-based chemotherapy.Over the past few decades,developments in immunotherapeutic strategies have provided newer insights into the treatment of gliomas.Immunotherapy is based on the principle of normalization or recovery of T cell-mediated anti-tumor immunoreaction.Different innovative strategies have been used;these include enhancement of immunogenicity by administration of tumor antigens or dendritic cell vaccines,replenishment of cytotoxic T cells by adoptive T cell transfer,repair of exhausted T cells by immune checkpoint inhibitors,and the use of other immune activators such as oncolytic viruses.However,many immunotherapy-based clinical trials did not meet the expected therapeutic endpoints in patients with glioma.Gliomas use unique strategies to generate an immune-suppressive microenvironment;these include limiting immunogenicity and repressing T cell infiltration or activation.This may be addressed by the incorporation of immunotherapy with standard therapy or by use of certain innovative approaches such as tumor-treating fields.In this review,we summarize the updated immunotherapies in glioma and discuss current limitations and future prospects.