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The detection of fast variations of the tera-electron volt (TeV) (10¹² eV) γ-ray flux, on time scales of days, from the nearby radio galaxy M87 is reported. These variations are about 10 times as fast as those observed in any other wave band and imply a very compact emission region with a dimension similar to the Schwarzschild radius of the central black hole. We thus can exclude several other sites and processes of the γ-ray production. The observations confirm that TeV γ rays are emitted by extragalactic sources other than blazars, where jets are not relativistically beamed toward the observer.

To determine whether severity and organ failure scores over the first 3 days in an ICU predict in-hospital mortality in onco-hematological malignancy patients. Retrospective study in a 22-bed medical ICU. 92 consecutive patients with onco-hematological malignancies including 20 hematopoietic stem cell transplantation (HSCT) patients (11 with allogenic HSCT). Simplified Acute Physiology Score (SAPS) II, Organ Dysfunction and/or Infection (ODIN) score, Logistic Organ Dysfunction System (LODS), and Sequential Organ Failure Assessment (SOFA) score were recorded on admission. The change in each score (Delta score) during the first 3 days in the ICU was calculated as follows: severity or organ failure score on day 3 minus severity or organ failure score on day 1, divided by severity or organ failure score on day 1. In-hospital mortality was 58%. Using multivariate analysis in-hospital mortality was predicted by all scores on day 1 and all Delta scores. Areas under the receiver operating characteristics curves were similar for SAPS II (0.78), ODIN (0.78), LODS (0.83), and SOFA (0.78) scores at day 1. They were also similar for DeltaSAPS II, DeltaODIN, DeltaLODS, and DeltaSOFA. Similar results were observed when excluding patients with allogenic HSCT. Severity and three organ failure scores on day 1 and Delta scores perform similarly in predicting in-hospital mortality in ICU onco-hematological malignancy patients but do not predict individual outcome. Decision to admit such patients to the ICU or to forgo life-sustaining therapies should not be based on these scores.

BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1 negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.

Translocations involving the BCL-6 gene are frequently observed in diffuse large B cell lymphoma, but have rarely been reported in follicular lymphoma (FL). We studied a distinct cohort of FLs with a 3q27/BCL-6 gene rearrangement, but lacking the t(14;18) translocation. In 13/15 cases, translocations involved the 3q27 and the 14q32 regions. All cases displayed a marked follicular growth pattern and, in some instances, a monocytoid component. Tumor cells were CD5(-) CD20(+) CD23(-) CD43(-) BCL-6(+), and in the main CD10 negative (n = 10, 71%) and BCL-2 negative (n = 11, 78%). When compared to 20 typical t(14;18)(+) FLs, the presence of large follicles (P = 0.01) and a CD10(-)/BCL-2(-) phenotype were more frequently observed (P = 0.001) in our cohort. Clonal mutations arising in the BCL-6 first intron were observed in 5/7 cases with evidence of intraclonal heterogeneity, consistent with a germinal center origin. No significant difference was found in comparison to t(14;18)(+) FL regarding age, sex, performance status, bone marrow involvement or overall survival. However, in the 3q27(+) FL group, a stage III/IV disease and a bulky mass were less frequently observed. This study indicates that 3q27(+) FL without t(14;18) translocation have peculiar clinico-pathologic features and may correspond to a rare and distinct subtype of lymphoma originating from the germinal center.

The Cherenkov Telescope Array (CTA) - an array of several tens of Cherenkov telescopes - is the next generation of ground-based instrument in the field of very high energy gamma-ray astronomy. The CTA observatory is expected to produce a main data stream for permanent storage of the order of 1-to-5 GB/s for about 1000 hours of observation per year, thus producing a total data volume of the order of several PB per year. The CPU time needed to calibrate and process one hour of data taking will be of the order of some thousands CPU hours with current technology. The high data rate of CTA, together with the large computing power requirements for Monte Carlo (MC) simulations, need dedicated computing resources. Massive MC simulations are needed to study the physics of cosmic-ray atmospheric showers as well as telescope response and performance for different detectors and layout configurations. Given these large storage and computing requirements, the Grid approach is well suited, and a vast number of MC simulations are already running on the European Grid Infrastructure (EGI). In order to optimize resource usage and to handle all production and future analysis activities in a coherent way, a high-level framework with advanced functionalities is desirable. For this purpose we have preliminarly evaluated the DIRAC framework for distributed computing and tested it for the CTA workload and data management systems. In this paper we present a possible implementation of a Distributed Computing Infrastructure (DCI) Computing Model for CTA as well as the benchmark test results of DIRAC.

Follicular lymphomas (FL) are closely associated with a t(14;18)(q32;q21) translocation, leading to a bcl2 protein over-production. This translocation probably constitutes a very early step in the development of the disease. Besides the cytogenetic assay, t(14;18) detection can be achieved using either Southern blot or polymerase chain reaction (PCR). Since 1990, several publications have reported discrepancies between the results of cytogenetic and molecular analysis of t(14;18). Using methods able to explore long DNA fragments, several authors reported breakpoints located outside the usual breakpoint regions. However, these techniques cannot be easily used in routine. The aim of this study was to develop a simple PCR assay to amplify rearrangements usually not detected in FL. We selected a group of 83 patients with a t(14;18) on cytogenetic analysis: using usual probes and primers, 54/83 (65.1%) showed a MBR rearrangement, 7/83 (8.4%) were mcr positive and 22/83 (26.5%) remained negative. Among these 22 rearrangements, nine could be detected using this new PCR assay. Four breakpoints were located in a 20 bp area suggesting a recurrent breakpoint cluster close to an Alu repetitive sequence. Finally, remaining negative cases (13/83, 15.6%) suggest that other breakpoints are located between the MBR and mcr regions.

The t(14;18)(q32;q21) translocation is closely associated with follicular lymphoma (FL), and is routinely assessed with molecular methods exploring BCL2 breakpoints for both diagnosis and minimal residual disease (MRD) monitoring. We and others have previously reported new recurrent breakpoints (3'BCL2 and 5'mcr) which could be easily analyzed. In this study, we characterized the BCL2 breakpoints in 113 untreated patients with t(14;18)-positive FL and correlated their location with the location of JH break and with the clinical features. Breakpoints were respectively located at the major breakpoint region (MBR) in 73 cases (65%), at the minor cluster region (mcr) in 10 cases (9%), at 3'BCL2 in 14 cases (12%) and at 5'mcr in seven cases (6%). Finally, the breakpoint could not be located in nine patients (8%). 5'mcr cases were associated with bulky and high-stage disease, with frequent extranodal involvement and bone marrow infiltration. Survival studies did not show any correlation between breakpoint location and clinical outcome. The joining JH6 segment was the most frequently involved whatever the breakpoint location. In conclusion, unusual BCL2 breakpoints are found in about 20% of newly diagnosed follicular lymphomas and their study should be considered in the investigation of BCL2-JH rearrangement. It was not possible, in this series, to demonstrate any correlation between breakpoint location and either initial characteristics of the disease or survival of the patients.

Gamma-ray bursts (GRBs) are brief flashes of γ-rays and are considered to be the most energetic explosive phenomena in the Universe1. The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow—produced by the interaction between the ejected matter and the circumburst medium—slows down, and a gradual decrease in brightness is observed2. GRBs typically emit most of their energy via γ-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments3. However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive4. Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow—ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and γ-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies