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Abstract: 

Glioblastoma is an aggressive brain cancer with high resistance to conventional therapies, killing 200,000 worldwide every year. Aneuploidy, the disbalance of chromosomal counts, is considered a significant development agent, being characterized in 90% of solid tumors and commonly regulated by the BUB1 and SMC1A genes. Understanding the biological pathways that drive tumor development and resistance becomes paramount in developing effective treatments. Thus, the following study investigated the genetic suppression of BUB1 and SMC1A in astrocytes to determine if aneuploidy could be induced. Human brain tissue samples of both healthy and patients with glioblastoma obtained underwent fluorescence-activated cell sorting for astrocyte isolation. To investigate aneuploid patterns, the study employed single-cell whole-genome sequencing, interphase Fluorescence In Situ Hybridization (FISH), and RNAscope to quantify chromosomal copy number alterations and aneuploidy frequencies. Additionally, in-vitro cell culturing experiments involving lentivirus-induced knockdown of BUB1 and SMC1A genes provided insights into gene expression changes, affirming the creation of an aneuploidic environment in astrocytes. The study identified large aneuploid frequencies in glioblastoma inflicted brain samples and significant knockdown of BUB1 and SMC1A (p<0.05), creating an pro-aneuploidic environment that can further be observed to identify the senescence associated secretory phenotype. Altogether, the study provides validation of significant gene knockdown and the establishment of a framework to explore potential therapeutic strategies for aggressive brain cancers like glioblastoma.

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