Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

The past 50 years have seen an accumulation of evidence suggesting that associative learning depends on high-level cognitive processes that give rise to propositional knowledge. Yet, many learning theorists maintain a belief in a learning mechanism in which links between mental representations are formed automatically. We characterize and highlight the differences between the propositional and link approaches, and review the relevant empirical evidence. We conclude that learning is the consequence of propositional reasoning processes that cooperate with the unconscious processes involved in memory retrieval and perception. We argue that this new conceptual framework allows many of the important recent advances in associative learning research to be retained, but recast in a model that provides a firmer foundation for both immediate application and future research.

This article presents a comprehensive survey of research concerning interactions between associative learning and attention in humans. Four main findings are described. First, attention is biased toward stimuli that predict their consequences reliably (). This finding is consistent with the approach taken by Mackintosh (1975) in his attentional model of associative learning in nonhuman animals. Second, the strength of this attentional bias is modulated by the value of the outcome (). That is, predictors of high-value outcomes receive especially high levels of attention. Third, the related but opposing idea that may result in increased attention to stimuli (Pearce & Hall, 1980), receives less support. This suggests that hybrid models of associative learning, incorporating the mechanisms of both the Mackintosh and Pearce-Hall theories, may not be required to explain data from human participants. Rather, a simpler model, in which attention to stimuli is determined by how strongly they are associated with significant outcomes, goes a long way to account for the data on human attentional learning. The last main finding, and an exciting area for future research and theorizing, is that and modulate both deliberate attentional focus, and more automatic attentional capture. The automatic influence of learning on attention does not appear to fit the traditional view of attention as being either or. Rather, it suggests a new kind of “derived” attention.

Cues that reliably predict an outcome in an initial phase of training (Phase 1) are learned faster in a second phase of training (Phase 2) than cues that were unreliable in Phase 1. This result is observed despite objectively equal relationships between the cues and the outcomes in Phase 2, and consequently constitutes a nonnormative bias in learning. The present experiments sought to confirm that this learned predictiveness effect is the product of attentional processes (Experiment 1), and to test further whether these processes are under voluntary control or are automatic in nature (Experiment 2). In addition to the usual outcome prediction measure, eye-gaze behavior was also monitored. The results indicated an important role for top-down strategic attentional processes in the learned predictiveness task. In contrast, no evidence for an automatic attentional bias was found.