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PNAS Papers on Alzheimer's Transcriptomes, Bladder Cancer Mutations, CRC Drivers

Researchers from the Hong Kong University of Science and Technology and elsewhere describe altered gene expression profiles in cell types in the prefrontal cortical brain samples from individuals with or without Alzheimer's disease. Based on differential analyses using single-nucleus transcriptome sequencing data for nearly 169,500 cells from post-mortem prefrontal cortex samples from a dozen individuals with Alzheimer's disease and nine unaffected control individuals, the team identified a group of neuroprotective glial cells that appear to be dialed down in Alzheimer's disease, along with angiogenic endothelial cells and related genes that are enhanced in those with the neurodegenerative disease. These and other results from the study "offer important insights into the therapeutic potential of targeting glial- and endothelial-specific pathways to restore brain homeostasis in [Alzheimer's disease]," they write.

A Rockefeller University team takes a look at the consequences of chromatin regulator and receptor tyrosine kinase signaling gene mutations in bladder cancer. Using RNA sequencing and other approaches, the researchers considered gene expression shifts in bladder cancer cell lines designed to carry a pair of alterations that were frequently found in muscle-invasive forms of bladder cancer profiled for the Cancer Genome Atlas, particularly loss of the UTX histone demethylase enzyme-coding gene and a co-occurring activation event involving the receptor tyrosine kinase FGFR3. From the altered expression profiles identified in their experiments, the authors suggest that "UTX loss and FGFR3 activation cooperate in bladder cells to reduce the expression of lumina genes, promoting a more basal, de-differentiated cellular state."

University of Amsterdam and Roche Innovation Center Basel investigators share findings from a study of the oncogenic transformation that leads to colorectal cancer (CRC) along the so-called "adenoma-carcinoma" sequence in the presence of mutations involving driver genes such as APC, KRAS, SMAD4, and TP53. After systematically introducing such common drive gene mutations into organoids developed from mouse and human small intestine samples, the team used labeled amino acid experiments, proliferation assays, and other strategies to follow messenger RNA translation. "[W]e found that each mutation governs the global translational capacity of the epithelial cells," the authors report. "Global translation is linked to known oncogenic hallmarks, including cell proliferation and growth upon accumulation of these mutations, posing the translational apparatus as a potential therapeutic target in CRC."