Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.info:eu-repo/semantics/publishedVersio

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Humming trains in seismology: an opportune source for probing the shallow crust

Link to published version:https://pubs.geoscienceworld.org/ssa/srl/article-abstract/92/2A/623/594056/Humming-Trains-in-Seismology-An-Opportune-Source?redirectedFrom=fulltextInternational audienceSeismologists are eagerly seeking new and preferably low‐cost ways to map and track changes in the complex structure of the top few kilometers of the crust. By understanding it better, they can build on what is known regarding important, practical issues. These include telling us whether imminent earthquakes and volcanic eruptions are generating telltale underground signs of hazard, about mitigation of induced seismicity such as from deep injection of wastewater, how the Earth and its atmosphere couple, and where accessible natural resources are. Passive seismic imaging usually relies on blind correlations within extended recordings of Earth’s ceaseless “hum” or coda of well‐mixed, small vibrations. In this article, we propose a complementary approach. It is seismic interferometry using opportune sources—specifically ones not stationary in time and moving in a well‐understood configuration. Its interpretation relies on an accurate understanding of how these sources radiate seismic waves, precise timing, careful placement of pairs of listening stations, and seismic phase differentiation (surface and body waves). Massive freight trains were only recently recognized as such a persistent, powerful cultural (human activity‐caused) seismic source. One train passage may generate a tremor with an energy output of a magnitude 1 earthquake and be detectable for up to 100 km from the track. We discuss the source mechanisms of train tremors and review the basic theory on sources. Finally, we present case studies of body‐ and surface‐wave retrieval as an aid to mineral exploration in Canada and to monitoring of a southern California fault zone. We believe noise recovery from this new signal source, together with dense data acquisition technologies such as nodes or distributed acoustic sensing, will deeply transform our ability to monitor activity in the shallow crust at sharpened resolution in time and space

An Automated Method for Developing a Catalog of Small Earthquakes Using Data of a Dense Seismic Array and Nearby Stations

We propose a new automated procedure for using continuous seismic waveforms recorded by a dense array and its nearby regional stations for P‐wave arrival identification, location, and magnitude estimation of small earthquakes. The method is illustrated with a one‐day waveform dataset recorded by a dense array with 99 sensors near Anza, California, and 24 surrounding regional stations within 50 km of the dense array. We search a wide range of epicentral locations and apparent horizontal slowness values (⁠0–15  s/km⁠) in the 15–25 Hz range and time shift the dense array waveforms accordingly. For each location–slowness combination, the average neighboring station waveform similarity (avgCC) of station pairs <150  m apart is calculated for each nonoverlapping 0.5 s time window. Applying the local maximum detection algorithm gives 966 detections. Each detection has a best‐fitting location–slowness combination with the largest avgCC. Of 331 detections with slowness <0.4  s/km⁠, 324 (about six times the catalog events and 98% accuracy) are found to be earthquake P‐wave arrivals. By associating the dense array P‐wave arrivals and the P‐ and S‐wave arrivals from the surrounding stations using a 1D velocity model, 197 detections (⁠∼4 times of the catalog events) have well‐estimated locations and magnitudes. Combining the small spacing of the array and the large aperture of the regional stations, the method achieves automated earthquake detection and location with high sensitivity in time and high resolution in space. Because no preknowledge of seismic‐waveform features or local velocity model is required for the dense array, this automated algorithm can be robustly implemented in other locations

An Automated Method for Developing a Catalog of Small Earthquakes Using Data of a Dense Seismic Array and Nearby Stations

We propose a new automated procedure for using continuous seismic waveforms recorded by a dense array and its nearby regional stations for P‐wave arrival identification, location, and magnitude estimation of small earthquakes. The method is illustrated with a one‐day waveform dataset recorded by a dense array with 99 sensors near Anza, California, and 24 surrounding regional stations within 50 km of the dense array. We search a wide range of epicentral locations and apparent horizontal slowness values (⁠0–15  s/km⁠) in the 15–25 Hz range and time shift the dense array waveforms accordingly. For each location–slowness combination, the average neighboring station waveform similarity (avgCC) of station pairs <150  m apart is calculated for each nonoverlapping 0.5 s time window. Applying the local maximum detection algorithm gives 966 detections. Each detection has a best‐fitting location–slowness combination with the largest avgCC. Of 331 detections with slowness <0.4  s/km⁠, 324 (about six times the catalog events and 98% accuracy) are found to be earthquake P‐wave arrivals. By associating the dense array P‐wave arrivals and the P‐ and S‐wave arrivals from the surrounding stations using a 1D velocity model, 197 detections (⁠∼4 times of the catalog events) have well‐estimated locations and magnitudes. Combining the small spacing of the array and the large aperture of the regional stations, the method achieves automated earthquake detection and location with high sensitivity in time and high resolution in space. Because no preknowledge of seismic‐waveform features or local velocity model is required for the dense array, this automated algorithm can be robustly implemented in other locations

Les vertébrés terrestres ont-ils joué un rôle dans l'épidémie du Chikungunya dans l'Océan Indien ?

National audienc

Safety and Tolerability of Whole Soybean Products: A Dose-Escalating Clinical Trial in Older Adults with Obesity

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70–85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at <30 g/day may be prudent for overall health and to prevent the exclusion of other food groups and nutrients in older adults with obesity