Alzheimer's disease (AD) is the most common neurodegenerative disease that is responsible for about one‐third of dementia cases worldwide. It is believed that AD is initiated with the deposition of Ab plaques in the brain. Genetic studies have shown that a high number of AD risk genes are expressed by microglia, the resident macrophages of brain. Common mode of action by microglia cells is neuroinflammation and phagocytosis. Moreover, it has been discovered that inflammatory marker levels are increased in AD patients. Recent studies advocate that neuroinflammation plays a major role in AD progression. Microglia have different activation profiles depending on the region of brain and stimuli. In different activation, profile microglia can generate either pro‐inflammatory or anti‐inflammatory responses. Microglia defend brain cells from pathogens and respond to injuries; also, microglia can lead to neuronal death along the way. In this review, we will bring the different roles played by microglia and microglia‐related genes in the progression of AD.
Background: Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach. Methods: High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma. RNAseq analysis supplemented this 128-compound screening to predict more efficacious and patient-specific drug combinations with additional tumor stemness evaluated using flow cytometry. In vivo PDX mouse models rapidly validated (50 days) and determined mutational influence alongside of drug efficacy. We present a representative GBM case of three tumors resected at initial presentation, at first recurrence without any treatment, and at a second recurrence following radiation and chemotherapy, all from the same patient. Results: Molecular and in vitro screening helped identify effective drug targets against several pathways as well as synergistic drug combinations of cobimetinib and vemurafenib for this patient, supported in part by in vivo tumor growth assessment. Each tumor iteration showed significantly varying stemness and drug resistance. Conclusions: Our integrative model utilizing molecular, in vitro, and in vivo approaches provides direct evidence of a patient’s tumor response drifting with treatment and time, as demonstrated by dynamic changes in their tumor profile, which may affect how one would address that drift pharmacologically.
The role of Aβ plaques and neurofibrillary tangles in Alzheimer's disease (AD) pathogenesis have recently come into question due to failure of many pharmaceutical agents targeting these deposits and detection of these misfolded proteins in normal human brains. Therefore, we investigated correlations between microglial activation and toll like receptor 4 (TLR4) and Lck/Yes novel tyrosine (LYN) kinase signaling in an AD mouse model.In this study, we used 5–6‐month‐old 5XFAD and wild type (WT) male and female mice. Immunohistochemistry (IHC) and flow cytometry (FC) were performed on their brains. Cognitive performance was assessed with the Barnes‐Maze.IHC showed more Ab aggregation in microglia of female 5XFAD mice compared to their male counterparts. Increased co‐localization of microglial TLR4 and LYN was also observed in AD more than WT and females more than males. IHC also suggests microglial phagocytosis of neurons in AD mice, which is supported by FC data. Our FC data also support the involvement of disease associated microglia (DAMs) in this process based on cytokine secretion. Cognitive assessment by the Barnes maze showed 5XFAD females performed worse than males.In this study, we investigated the relationship between microglial TLR4 and LYN kinase in 5XFAD male and females. Our data reveals a correlation between microglial TLR4 and LYN co‐localization and AD pathogenesis, more in females than males. Targeting microglial TLR4 and Lyn in DAMs may offer new therapeutic opportunities in the treatment of AD.
Introduction: The pioneer transcriptional factors (PTFs) of the Oct3/4 network including Oct3/4, Nanog, Sox2, Sall4 (ONSS), have been associated with breast cancer. Regulation of ONSS and other factors in this network were assessed for their role in malignancy. Methods: Triple negative breast cancer cell line (MDA-MB-231) transfected with human Oct3/4-GFP promoter was sorted using FACS. Differentially expressed genes (DEGs) were identified using qPCR and microarray. 3D mammospheres (CSC) from Oct3/4(+) cells were assessed for stable Oct3/4 expression. Tumor seeding and lung metastatic potential of Oct3/4(+) cells were assessed in immunocompromised mice. DEGs in the tumors were assessed with respect to implanted tissue (SQ, lungs or brain), recurrence, and metastases. Expression of CD44+/CD24- was evaluated using flow cytometry. Resistance of Oct3/4(+) cells to paclitaxel was assessed using MTS assay. Results: Oct3/4-GFP expression was stable in mammospheres. Oct3/4(+) cells showed 25 DEGs and significant resistance to paclitaxel when compared to non-transfected cells. Upregulated growth and developmental genes included Gata6, FoxA2, Sall4, Zic2, H2afJ, Stc1 and Bmi1. The Oct3/4(+) cells also showed enhanced tumorigenic potential and aggressive growth in immunocompromised mice. Additionally, this modulated transcriptome of the Oct3/4 (+) cells showed further upregulation of several genes in metastatic lung lesions in mice (> 5 fold) compared to orthotopic tumors including Oct4A, Bmi1, Ezh2, Klf5, Hox7B, Gja1, Stc1, Amigo2 and Dkk1. Serially re-implanting tumors in mice as a model of recurrence and metastasis highlighted Sall4, c-Myc, Mmp1, Mmp9 and Dkk1 genes in maintaining an upregulated expression specifically in metastatic lesions and a 2-fold higher expression of stem cell phenotype markers (CD44+/CD24-). Overall Oct3/4 expression in tumors in lungs, brain and metastases were significantly higher than orthotopic mammary fat pad tumors. Additionally, the transcriptome was most upregulated in brain except for Gja1 and H2faJ, indicating tissue-specific regulation of this transcriptome. Conclusion: ONSS and other Oct3/4 related factors may drive the differentiation and maintenance of breast cancer stem cells and may promote their tumorigenic potential and resistance to drugs such as paclitaxel. However, there is tissue-specific heterogeneity in the differential upregulation of this transcriptome as well stemness phenotype of tumors in these tissues.
Adaptive plasticity of Breast Cancer stem cells (BCSCs) is strongly correlated with cancer progression and resistance, leading to a poor prognosis. In this study, we report the expression profile of several pioneer transcription factors of the Oct3/4 network associated with tumor initiation and metastasis. In the triple negative breast cancer cell line (MDA-MB-231) stably transfected with human Oct3/4-GFP, differentially expressed genes (DEGs) were identified using qPCR and microarray, and the resistance to paclitaxel was assessed using an MTS assay. The tumor-seeding potential in immunocompromised (NOD-SCID) mice and DEGs in the tumors were also assessed along with the intra-tumor (CD44+/CD24-) expression using flow cytometry. Unlike 2-D cultures, the Oct3/4-GFP expression was homogenous and stable in 3-D mammospheres developed from BCSCs. A total of 25 DEGs including Gata6, FoxA2, Sall4, Zic2, H2afJ, Stc1 and Bmi1 were identified in Oct3/4 activated cells coupled with a significantly increased resistance to paclitaxel. In mice, the higher Oct3/4 expression in tumors correlated with enhanced tumorigenic potential and aggressive growth, with metastatic lesions showing a >5-fold upregulation of DEGs compared to orthotopic tumors and variability in different tissues with the highest modulation in the brain. Serially re-implanting tumors in mice as a model of recurrence and metastasis highlighted the sustained upregulation of Sall4, c-Myc, Mmp1, Mmp9 and Dkk1 genes in metastatic lesions with a 2-fold higher expression of stem cell markers (CD44+/CD24-). Thus, Oct3/4 transcriptome may drive the differentiation and maintenance of BCSCs, promoting their tumorigenic potential, metastasis and resistance to drugs such as paclitaxel with tissue-specific heterogeneity.
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