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This Week in Nature: Feb 14, 2019

In this week's Nature Medicine, a team led by scientists from Columbia University presents a study identifying multiple genomic features that influence how glioblastoma (GBM) patients respond to anti-PD-1 immune checkpoint inhibitor therapy, as well as the evolutionary patterns of such tumors in response to immunotherapy. The researchers longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors such as Bristol-Myers Squibb's Opdivo (nivolumab). "Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations in responders," they write. "Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes, as well as with differences in T cell clonal diversity and tumor microenvironment profiles." 

And in Nature Biotechnology, Massachusetts General Hospital investigators describe a novel CRISPR-Cas12a variant with an improved targeting range for gene, epigenetic, and base editing. The engineered nuclease can be used to target protospacer adjacent motifs previously inaccessible, and improves the efficiency of multiplex gene editing, endogenous gene activation, and C-to-T base editing, the authors write. Additionally, a high-fidelity version of the nuclease was developed with reduced off-target effects. This work, they add, provides an optimized version of Cas12a that should "enable wider application of Cas12a enzymes for gene and epigenetic editing." GenomeWeb has more on this, here.

Meanwhile, in Nature Microbiology, researchers from Karius and Stanford University describe the validation of a blood-based next-generation sequencing test for infectious disease that can identify and quantify microbial cell-free DNA in plasma from 1,250 clinically relevant bacteria, DNA viruses, fungi, and eukaryotic parasites. The test — which is marketed by the company — showed 93.7 percent agreement with blood culture in a cohort of 350 patients with a sepsis alert and identified an independently adjudicated cause of the sepsis alert more often than all of the microbiological testing combined. "Among the 166 samples adjudicated to have no sepsis aetiology identified by any of the testedmethods, sequencing identified microbial cell-free DNA in 62, likely derived from commensal organisms and incidental findings unrelated to the sepsis alert," the researchers write. GenomeWeb also covers this, here.