In addition to parenchymal amyloid-beta (Abeta) plaques, Alzheimer's disease (AD) is characterized by Abeta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Abeta (VAbeta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Abeta antibodies may clear parenchymal amyloid but increase VAbeta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAbeta and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VAbeta and microhemorrhage in PDAPP mice by comparing antibodies with different Abeta epitopes (3D6, Abeta(1-5); 266, Abeta(16-23)) and performing a 3D6 dose-response study. VAbeta and microhemorrhage were assessed using concomitant Abeta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAbeta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAbeta was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with Abeta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAbeta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAbeta. These observations raise the possibility that Abeta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.
Although genetic predisposition plays a major role in the progression of systemic lupus erythematosus (SLE) and its variation in symptoms, the precise relationships between genetic changes and disease status are not well understood. Here, to demonstrate the effect of a single gene mutation on disease etiology, we examined two mouse models of SLE with the same genetic background but different Fas genes. Mice with the Faslpr gene developed severe SLE with renal dysfunction and inflammatory responses in the lung and kidney. By contrast, mice with the Fas+ gene showed disease-related abnormalities in the liver and joints. Patterns of inflammatory disease markers differed across organs between the two lines of mice. Faslpr mice showed greater MMP signals in the kidney and IL-11 signals in the lung than Fas+ mice. Fas+ mice had higher IL-11 signal intensity in the knee region and higher CXCR4 signal intensity in the liver than Faslpr mice. Our results exemplify the complexity of disease and suggest the need for individualized target-specific treatment regimens. Strengths and Limitations of this Study: Fas gene is a well characterized gene in this disease. The molecular components in human disease need more clinical data. Keywords: Systemic lupus erythematosus, genetic mutation, molecular abnormality, molecular imaging, molecular medicine.
Abstract Background Acute myeloid leukaemia (AML) are a bunch of malignant tumors derived from hematopoietic stem cells, characterized by high morbidity, high relapse rate and high lethality. Recent years have demonstrated the association between aberrant glycosylation and tumors, but how aberrant glycosylation affects the heterogeneity and prognosis of AML patients remains to be explored. Methods Comprehensive single-cell sequencing analyses (scRNA-seq) and transcriptome expression analyses were conducted on the GSE235857 and GSE37642 datasets, with pertinent data on acute myeloid leukemia (AML) acquired from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Twelve genes were identified with abnormal glycosylation modifications using the Cox regression, Stepwise regression and LASSO regression analyses for construction of a prognostic model for patients with AML. In addition, the tumor immune escape was stronger in patients with highly glycosylated subgroups, and expression levels of key genes were verified through single-cell sequencing. Results Through scRNA-seq analysis, we identified 12 glycosylation-related genes associated with AML prognosis in patients. Risk profiles were then established for these 12 genes, revealing a primary association with both glycosylation and EMT. Furthermore, patients exhibiting high glycosylation modifications displayed a stronger tendency towards immune escape and poorer immunotherapy outcomes. Drug target screening subsequently identified several candidate agents for therapeutic intervention of hyper-glycosylation modifications. Finally, Identification and validation of the presence of 12 core genes related to glycosylation in AML patients by scRNA-seq. Conclusions The constructed risk models based on abnormal glycosylation modifications can effectively predict the prognosis of AML. In-depth study of abnormal glycosylation modifications in AML is advocated to further explore the response of AML to immunotherapy andprovides new insights into the diagnosis and management of AML.
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