Cubillo, A. | Search bioRxiv

bioRxiv2020

Intra-individual variability in task performance after cognitive training is associated with long-term outcomes in children

The benefits and mechanistic effects of working memory training in children are the subject of much research and debate. The cumulative evidence indicates that training can alter brain structure and function in the short term and have lasting effects on behaviour. We show that five weeks of working memory training led to greater activity in prefrontal and striatal brain regions, better accuracy, and reduced intra-individual variability in response times. The reduction in intra-individual variability can be explained by changes to the evidence accumulation rates and thresholds in a sequential sampling decision model. Critically, intra-individual variability was more closely associated with academic skills and mental health 6-12 months after the end of training than task accuracy. These results indicate that intra-individual variability may be a useful way to quantify the immediate impact of cognitive training interventions and predict the future emergence of academic and socioemotional skills.

neuroscience↗

bioRxiv2017

Whole-exome sequencing of plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and enables the discovery of mutated KDR/VEGFR2 receptors as modulators of anti-angiogenic therapies.

The non-invasive detection of cancer mutations is a breakthrough in oncology. Here, we applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens including VEGFR inhibitors. Using WES-cfDNA, we could detect 73% (54/74) of the somatic mutations uncovered by WES-tumor including a variety of mutation types: frameshift (indels), missense, noncoding (splicing), and nonsense mutations. Additionally, WES-cfDNA discovered 14 high-confidence somatic mutations not identified by WES-tumor. Importantly, in the absence of the tumor specimen, WES-cfDNA could identify 68 of the 88 (77.3%) total mutations that could be identified by both techniques. Of tumor biology relevance, we identified the novel KDR/VEGFR2 L840F somatic mutation, which we showed was a clonal mutation event in this tumor. Comprehensive in vitro and in vivo functional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas the KDR/VEGFR2 hot-spot mutant R1032Q confers sensitivity to cabozantinib. Moreover, we found a 1-3% of recurrent KDR somatic mutations across large and non-overlapping cancer sequencing projects, and the majority of these mutations were located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK, suggesting a functional role.\n\nIn summary, the current study highlights the capability of exomic sequencing of cfDNA from plasma of cancer patients as a powerful platform for somatic landscape analysis and discovery of resistance-associated cancer mutations. Because of its advantage to generate results highly concordant to those of tumor sequencing without the hurdle of conventional tumor biopsies, we anticipate that WES-cfDNA will become frequently used in oncology. Moreover, our study identified for the first-time KDR/VEGFR2 somatic mutations as potential genetic biomarkers of response to anti-angiogenic cancer therapies and will serve as reference for further studies on the topic.

cancer biology↗