Although tight junctions between human brain microvascular endothelial cells in the blood-brain barrier prevent molecules or cells in the bloodstream from entering the brain, in Alzheimer's disease, peripheral blood monocytes can ''open'' these tight junctions and trigger subsequent transendothelial migration. However, the mechanism underlying this migration is unclear. Here, we found that the CSF2RB, but not CSF2RA, subunit of the granulocyte-macrophage colony-stimulating factor receptor was overexpressed on monocytes from Alzheimer's disease patients. CSF2RB contributes to granulocyte-macrophage colony-stimulating factor-induced transendothelial monocyte migration. Granulocyte-macrophage colony-stimulating factor triggers human brain microvascular endothelial cells monolayer tight junction disassembly by downregulating ZO-1 expression via transcription modulation and claudin-5 expression via the ubiquitination pathway. Interestingly, intracerebral granulocyte-macrophage colony-stimulating factor blockade abolished the increased monocyte infiltration in the brains of APP/PS1 Alzheimer's disease model mice. Our results suggest that in Alzheimer's disease patients, high granulocyte-macrophage colony-stimulating factor levels in the brain parenchyma and cerebrospinal fluid induced blood-brain barrier opening, facilitating the infiltration of CSF2RB-expressing peripheral monocytes across blood-brain barrier and into the brain. CSF2RB might be useful as an Alzheimer's disease biomarker. Thus, our findings will help to understand the mechanism of monocyte infiltration in Alzheimer's disease pathogenesis.
Adoptive cell therapy (ACT), including tumor‐infiltrating lymphocytes (TILs), T cell receptor engineered T cell (TCR‐T), and chimeric antigen receptor engineered T cell (CAR‐T), has shown significant clinical benefits for cancer treatment. However, all of these ACT therapies are associated with toxicities from mild to life threatening in clinic. Common ACT‐related toxicities include cytokine release syndrome (CRS) resulting from immune activation, neurological toxicity, on‐target/off tumor or off‐target toxicities, and toxicities associated with lymphodepletion preconditioning and high does IL‐2 administration. This review summarizes clinical manifestations of adverse events associated with ACT treatment and discusses the underlying pathological mechanisms. Moreover, challenges and opportunities of managing ACT‐related toxicities have been discussed to give an indication of how to improve the safety of ACT treatment without dampening the therapeutic effect.
Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid tumors, including melanomas, to identify potential drug targets. However, the association between clinical outcomes and the molecular alterations has not yet been fully clarified. We have analyzed the genetic alterations of 108 malignant melanoma patients using the OncoCare panel, which covers 559 genes. Combining clinical features with genetic analysis, we found that patients carrying both POLD1/ALOX12B or POLD1/PTPRT mutations had a significantly lower survival rate. A model was also established to predict side effects through a combination analysis of clinical data and somatic variants, yielding an area under the receiver operating characteristic curve (AUROC) score of 0.87. In addition, we also found that patients with the POLE mutation had a significantly worse clinical outcome to chemotherapy, while patients with the SOX9 mutation had a significantly worse response to immunotherapy. Overall, these results demonstrate the benefits of applying NGS clinical panels and shed light on future directions of personalized therapeutics for the treatment of melanoma.
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