Assessment of Minimal Residual Disease in Standard-Risk AML

BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.)

Extragalactic Radio Continuum Surveys and the Transformation of Radio Astronomy

Next-generation radio surveys are about to transform radio astronomy by discovering and studying tens of millions of previously unknown radio sources. These surveys will provide new insights to understand the evolution of galaxies, measuring the evolution of the cosmic star formation rate, and rivalling traditional techniques in the measurement of fundamental cosmological parameters. By observing a new volume of observational parameter space, they are also likely to discover unexpected new phenomena. This review traces the evolution of extragalactic radio continuum surveys from the earliest days of radio astronomy to the present, and identifies the challenges that must be overcome to achieve this transformational change.Comment: To be published in Nature Astronomy 18 Sept 201

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

A quantitative approach to study indirect effects among disease proteins in the human protein interaction network

<p>Abstract</p> <p>Background</p> <p>Systems biology makes it possible to study larger and more intricate systems than before, so it is now possible to look at the molecular basis of several diseases in parallel. Analyzing the interaction network of proteins in the cell can be the key to understand how complex processes lead to diseases. Novel tools in network analysis provide the possibility to quantify the key interacting proteins in large networks as well as proteins that connect them. Here we suggest a new method to study the relationships between topology and functionality of the protein-protein interaction network, by identifying key mediator proteins possibly maintaining indirect relationships among proteins causing various diseases.</p> <p>Results</p> <p>Based on the i2d and OMIM databases, we have constructed (i) a network of proteins causing five selected diseases (DP, disease proteins) plus their interacting partners (IP, non-disease proteins), the DPIP network and (ii) a protein network showing only these IPs and their interactions, the IP network. The five investigated diseases were (1) various cancers, (2) heart diseases, (3) obesity, (4) diabetes and (5) autism. We have quantified the number and strength of IP-mediated indirect effects between the five groups of disease proteins and hypothetically identified the most important mediator proteins linking heart disease to obesity or diabetes in the IP network. The results present the relationship between mediator role and centrality, as well as between mediator role and functional properties of these proteins.</p> <p>Conclusions</p> <p>We show that a protein which plays an important indirect mediator role between two diseases is not necessarily a hub in the PPI network. This may suggest that, even if hub proteins and disease proteins are trivially of great interest, mediators may also deserve more attention, especially if disease-disease associations are to be understood. Identifying the hubs may not be sufficient to understand particular pathways. We have found that the mediators between heart diseases and obesity, as well as heart diseases and diabetes are of relatively high functional importance in the cell. The mediator proteins suggested here should be experimentally tested as products of hypothetical disease-related proteins.</p

Cold streams in early massive hot haloes as the main mode of galaxy formation

The massive galaxies in the young universe, ten billion years ago, formed stars at surprising intensities. Although this is commonly attributed to violent mergers, the properties of many of these galaxies are incompatible with such events, showing gas-rich, clumpy, extended rotating disks not dominated by spheroids (Genzel et al. 2006, 2008). Cosmological simulations and clustering theory are used to explore how these galaxies acquired their gas. Here we report that they are stream-fed galaxies, formed from steady, narrow, cold gas streams that penetrate the shock-heated media of massive dark matter haloes (Dekel & Birnboim 2006; Keres et al. 2005). A comparison with the observed abundance of star-forming galaxies implies that most of the input gas must rapidly convert to stars. One-third of the stream mass is in gas clumps leading to mergers of mass ratio greater than 1:10, and the rest is in smoother flows. With a merger duy cycle of 0.1, three-quarters of the galaxies forming stars at a given rate are fed by smooth streams. The rarer, submillimetre galaxies that form stars even more intensely are largely merger-induced starbursts. Unlike destructive mergers, the streams are likely to keep the rotating disk configuration intact, although turbulent and broken into giant star-forming clumps that merge into a central spheroid (Noguchi 1999; Genzel et al. 2008, Elmegreen, Bournaud & Elmegreen 2008, Dekel, Sari & Ceverino 2009). This stream-driven scenario for the formation of disks and spheroids is an alternative to the merger picture.Comment: Improved version, 25 pages, 13 figures, Letter to Nature with Supplementary Informatio

Analyzing Childlessness

Childlessness has been on the rise in many European societies. In Germany, the UK, Austria, the Netherlands, and Switzerland, childlessness has increased starting with the 1950s cohorts. In these countries, about 20 % of the women born around 1965 will remain childless. In southern Europe and the former state-socialist countries of Central and Eastern Europe, the rise in levels of childlessness is a more recent phenomenon. Yet among younger cohorts in these countries, childlessness has reached levels of 15 % or higher. In this introductory chapter, we summarize the long-term trends in childlessness and discuss the differences between European countries in the prevalence of childlessness. We also outline the structure and the logic of this volume

Tensile Properties of the Murine Ventral Vertical Midline Incision

In clinical surgery, the vertical midline abdominal incision is popular but associated with healing failures. A murine model of the ventral vertical midline incision was developed in order to study the healing of this incision type.The strength of the wild type murine ventral abdominal wall in the midline was contained within the dermis; the linea alba made a negligible contribution. Unwounded abdominal wall had a downward trend (nonsignificant) in maximal tension between 12 and 29 weeks of age. The incision attained 50% of its final strength by postoperative day 40. The maximal tension of the ventral vertical midline incision was nearly that of unwounded abdominal wall by postwounding day 60; there was no difference in unwounded vs. wounded maximal tension at postwounding day 120.After 120 days of healing, the ventral vertical midline incision in the wild type mouse was not significantly different from age-matched nonwounded controls. About half of the final incisional strength was attained after 6 weeks of healing. The significance of this work was to establish the kinetics of wild type incisional healing in a model for which numerous genotypes and genetic tools would be available for subsequent study

A Longitudinal Test of the Demand–Control Model Using Specific Job Demands and Specific Job Control

# The Author(s) 2010. This article is published with open access at Springerlink.com Background Supportive studies of the demand–control (DC) model were more likely to measure specific demands combined with a corresponding aspect of control. Purpose A longitudinal test of Karasek’s (Adm Sci Q. 24:285–308, 1) job strain hypothesis including specific measures of job demands and job control, and both selfreport and objectively recorded well-being. Method Job strain hypothesis was tested among 267 health care employees from a two-wave Dutch panel survey with a 2-year time lag. Results Significant demand/control interactions were found for mental and emotional demands, but not for physical demands. The association between job demands and job satisfaction was positive in case of high job control, whereas this association was negative in case of low job control. In addition, the relation between job demands and J. de Jonge (*