Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples. Consequently, we were able to detect copy number changes, such as an interstitial deletion of BCOR, three MLL partial tandem duplications, and a novel KRAS amplification. With regards to coding mutations, we identified likely oncogenic variants in 41 of 42 samples. NPM1 mutations were the most frequent, followed by FLT3, DNMT3A and TET2. NPM1 and FLT3 indels were reported with good efficiency. We also showed that DNMT3A mutations can persist post-chemotherapy and in 2 cases studied at diagnosis and relapse, we were able to delineate the dynamics of tumor evolution and give insights into order of acquisition of variants. HaloPlex is a quick and reliable target enrichment method that can aid diagnosis and prognostic stratification of acute myeloid leukemia patients.This project was funded by the Wellcome Trust. NB is a fellow of the European Hematology Association and was supported by the Academy of Medical Sciences. EP is a European Hematology Association Advanced Research Fellow. GV is a Wellcome Trust Senior Fellow in Clinical Science. IV is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal

Episodes of intensified biological productivity in the subtropical Atlantic Ocean during the termination of the Middle Eocene Climatic Optimum (MECO)

The Middle Eocene Climatic Optimum (MECO) is an ~500 kyr interval of pronounced global warming from which the climate system recovered in <50 kyr. The deep-sea sedimentary record can provide valuable insight on the marine ecosystem response to this protracted global warming event and consequently on the ecological changes during this time. Here we present new benthic foraminiferal assemblage data from Ocean Drilling Program Site 1051 in the subtropical North Atlantic, spanning the MECO and post-MECO interval (41.1 to 39.5 Ma). We ␣nd little change in the species composition of benthic foraminiferal assemblages during the studied interval, suggesting that the rate of environmental change was gradual enough that these organisms were able to adapt. However, we identify two transient intervals associated with peak warming (higher-productivity interval (HPI)-1; 40.07–39.96 Ma) and shortly after the MECO (HPI-2; 39.68–39.55 Ma), where benthic foraminiferal accumulation rates increase by an order of magnitude. These HPIs at Site 1051 appear to coincide with intervals of strengthened productivity in the Tethys, Southern Ocean, and South Atlantic, and we suggest that an intensi␣ed hydrological cycle during the climatic warmth of the MECO was responsible for eutrophication of marine shelf and slope environments

The Sardinia Radio Telescope . From a technological project to a radio observatory

Context. The Sardinia Radio Telescope (SRT) is the new 64 m dish operated by the Italian National Institute for Astrophysics (INAF). Its active surface, comprised of 1008 separate aluminium panels supported by electromechanical actuators, will allow us to observe at frequencies of up to 116 GHz. At the moment, three receivers, one per focal position, have been installed and tested: a 7-beam K-band receiver, a mono-feed C-band receiver, and a coaxial dual-feed L/P band receiver. The SRT was officially opened in September 2013, upon completion of its technical commissioning phase. In this paper, we provide an overview of the main science drivers for the SRT, describe the main outcomes from the scientific commissioning of the telescope, and discuss a set of observations demonstrating the scientific capabilities of the SRT. Aims: The scientific commissioning phase, carried out in the 2012-2015 period, proceeded in stages following the implementation and/or fine-tuning of advanced subsystems such as the active surface, the derotator, new releases of the acquisition software, etc. One of the main objectives of scientific commissioning was the identification of deficiencies in the instrumentation and/or in the telescope subsystems for further optimization. As a result, the overall telescope performance has been significantly improved. Methods: As part of the scientific commissioning activities, different observing modes were tested and validated, and the first astronomical observations were carried out to demonstrate the science capabilities of the SRT. In addition, we developed astronomer-oriented software tools to support future observers on site. In the following, we refer to the overall scientific commissioning and software development activities as astronomical validation. Results: The astronomical validation activities were prioritized based on technical readiness and scientific impact. The highest priority was to make the SRT available for joint observations as part of European networks. As a result, the SRT started to participate (in shared-risk mode) in European VLBI Network (EVN) and Large European Array for Pulsars (LEAP) observing sessions in early 2014. The validation of single-dish operations for the suite of SRT first light receivers and backends continued in the following year, and was concluded with the first call for shared-risk early-science observations issued at the end of 2015. As discussed in the paper, the SRT capabilities were tested (and optimized when possible) for several different observing modes: imaging, spectroscopy, pulsar timing, and transients

Circulating biomarkers in familial cerebral cavernous malformation

Background Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression.Methods Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n =17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches.Findings Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM.Interpretation Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease