In Science this week, a team from Memorial Sloan-Kettering Cancer Center reports on its discovery of genetic mutations that improve the clinical response to the cancer drug everolimus. The researchers sequenced the genome of a metastatic bladder cancer patient who had shown a complete and long-lasting response to the drug, which targets the signaling protein mTORC1. They discovered mutations in TSC1, a gene associated with mTORC1 dependence, and sequenced it in other bladder cancer patients, and found that the mutations were associated with better responses to everolimus. The results "suggest that mTORC1-directed therapies may be most effective in cancer patients whose tumors harbor TSC1 somatic mutations, and demonstrate the feasibility of using whole-genome and capture-based sequencing methodologies in the clinical setting to identify previously unrecognized biomarkers of drug response in genetically heterogeneous solid tumors," the researchers write.
Also in Science, investigators from the University of Geneva and their collaborators show how the RNA-binding protein Cold-Inducible RNA-Binding Protein, or CIRP, affects daily body temperature rhythms. In in vitro experiments, they show that simulated body temperature cycles, but not peripheral oscillators, controlled the rhythmic expression of CIRP. "In turn, loss-of-function experiments indicated that CIRP was required for high-amplitude circadian gene expression." The researchers identified the circadian oscillator protein CLOCK is a CIRP binding partner, and found that "CLOCK accumulation was strongly reduced in CIRP-depleted fibroblasts." They say that CIRP, through its regulation of CLOCK expression, is key to mammalian circadian timing system.
Kyoto University investigators describe the discovery of two genes in sea squirts that coordinate during the animals' development. Looking at the genes Pinhead and Admp, which neighbor each other in most bilaterally symmetrical animals, the researchers found that the first "directly disturbs" the action of the second in order to establish the dorsoventral axis of the trunk epidermis in sea squirt embryos. The data "suggest that this dual negative regulatory mechanism is widely conserved in animals."
Over in Science Translational Medicine, NIH researchers recount using whole-genome sequencing to track a hospital-based outbreak of carbapenem-resistant Klebsiella pneumonia in real time and at a higher resolution than would have been possible with other methods. "Integrated genomic and epidemiological analysis traced the outbreak to three independent transmissions from a single patient who was discharged 3 weeks before the next case became clinically apparent," the researchers write. "Additional genomic comparisons provided evidence for unexpected transmission routes, with subsequent mining of epidemiological data pointing to possible explanations for these transmissions."