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

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4–6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000–200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30–60% of haematopoiesis was accounted for by 12–18 independent clones, each contributing 1–34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

Purpose: Although Src family kinase (SFK) inhibitors are now in clinical trials for the treatment of androgen-independent prostate cancer (AIPC), there are no studies relating SFK activation to patient survival. This study was designed to determine if SFK activation was up-regulated with the development of AIPC and if patients could be selected who were more likely to respond to therapy. Experimental Design: A unique cohort of matched prostate tumor samples, taken before hormone deprivation therapy and following hormone relapse, was used to determine by immunohistochemistry on an individual patient basis if SFK activity changed with progression to AIPC and whether this related to patient outcome measures. Using matched, hormone-sensitive and hormone-refractory cell lines, we determined if hormone status affected the way prostate cancer cells respond to suppression of SFK activity by the small-molecule inhibitor dasatinib.Results: In the current study, 28% of patients with AIPC exhibited an increase in SFK activity in prostate cancer tissue, these patients had significantly shorter overall survival (P < 0.0001), and activated SFK expression correlated with the presence of distant metastases. Dasatinib inhibited phosphorylation of Src and Lyn and the downstream substrate FAK in hormone-sensitive and hormone-refractory cell lines. Although migration was reduced by dasatinib in both cell lines, proliferation of hormone-refractory cells only was inhibited. Conclusion: Appropriate patient selection may allow better targeting of prostate cancer patients who are likely to respond to the treatment with SFK inhibitors at the same time improving the outcome of clinical trials.Prostate cancer is the most common cancer in men and is the second leading cause of cancer-related deaths in men in the United States and United Kingdom (1). Treatment options for locally advanced and metastatic prostate cancer are limited to androgen deprivation therapy or surgical castration. Unfortunately, nearly all of these patients eventually develop androgenindependent prostate cancer (AIPC) for which currently there are no established effective therapies.Our understanding of the mechanisms involved in the development of AIPC has considerably improved over the last decade. When deprived of androgen stimulation, androgensensitive prostate cancer (ASPC) cells develop the ability to survive and thrive by up-regulating oncogenic pathways where tyrosine kinases often play a crucial role (2). The nonreceptor tyrosine kinase Src is thought to facilitate the interaction between intracellular molecular cascades as well as form complexes with the androgen receptor (AR), which is expressed by the majority of AIPC cells. Tyrosine phosphorylation is an important factor in the regulation of AR activity resulting in translocation of the receptor into the nucleus and increase in DNA synthesis. Src activation by growth factors in prostate cancer cells has been shown to correlate with AR tyrosine phosphorylation, especially under androgen-depleted condi...

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As molecular scientists have made progress in their ability to engineer nano-scale molecular structure, we are facing new challenges in our ability to engineer molecular dynamics (MD) and flexibility. Dynamics at the molecular scale differs from the familiar mechanics of everyday objects, because it involves a complicated, highly correlated, and threedimensional many-body dynamical choreography which is often non-intuitive even for highly trained researchers. We recently described how interactive molecular dynamics in virtual reality (iMD-VR) can help to meet this challenge, enabling researchers to manipulate real-time MD simulations of flexible structures in 3D. In this article, we outline various efforts to extend immersive technologies to the molecular sciences, and we introduce 'Narupa', a flexible, opensource, multi-person iMD-VR software framework which enables groups of researchers to simultaneously cohabit realtime simulation environments to interactively visualize and manipulate the dynamics of molecular structures with atomic-level precision. We outline several application domains where iMD-VR is facilitating research, communication, and creative approaches within the molecular sciences, including training machines to learn reactive potential energy surfaces (PESs), biomolecular conformational sampling, protein-ligand binding, reaction discovery using 'on-the-fly' quantum chemistry, and transport dynamics in materials. We touch on iMD-VR's various cognitive and perceptual affordances, and how these provide research insight for molecular systems. By synergistically combining human spatial reasoning and design insight with computational automation, technologies like iMD-VR have the potential to improve our ability to understand, engineer, and communicate microscopic dynamical behavior, offering the potential to usher in a new paradigm for engineering molecules and nano-architectures.