La grammaire comparée dans l'enseignement secondaire - Une expérience suédoise

Maury Lucien. La grammaire comparée dans l'enseignement secondaire - Une expérience suédoise. In: Revue internationale de l'enseignement, tome 49, Janvier-Juin 1905. pp. 391-395

La grammaire comparée dans l'enseignement secondaire - Une expérience suédoise

Maury Lucien. La grammaire comparée dans l'enseignement secondaire - Une expérience suédoise. In: Revue internationale de l'enseignement, tome 49, Janvier-Juin 1905. pp. 391-395

Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report

International audienceIntroduction T-cell acute lymphoblastic leukemia (T-ALL) is an orphan disease diagnosed mostly in adolescent and young adults. In adult population, 5-10% of T-ALL patients (pts) will be primary refractory and 30-40% will relapse. In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration. On behalf of the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), we launched the ALL-TARGET project combining a precision medicine platform dedicated to R/R T-ALL and T-cell lymphoblastic lymphoma (T-LL), and an observatory to evaluate therapeutic proposals based on mutational profile and intracellular signaling pathways alterations. Objectives and methods Leukemic samples from pts with R/R T-ALL/LL were shipped to the GRAALL T-ALL central laboratory in France (V. Asnafi, Hôpital Necker). Biological characterization comprised oncogenetic, phenotypic and in some cases functional analysis. Clinical data from R/R T-ALL/LL pts were collected in a real-life observatory (NCT05832125). Adults pts were eligible if an oncogenetic characterization was available at diagnosis or relapse, and if they received a salvage, either with conventional therapy or with a targeted therapeutic option (TTO). For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7R ALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3K ALT). The ALL-TARGET Observatory primary endpoint was overall response rate (ORR) including complete remission (CR), CR with incomplete hematological recovery and partial response. We report here the results of the first pts included, with a focus on those who received TTOs as salvage therapy. Results Eighty-nine were analyzed, including 80 T-ALL and 9 T-LL. Sex ratio was 3 and median age at diagnosis was 37.5y, and 51y at the time of the first TTO. Seventy-one pts were in relapse (79.7%) and 18 primary refractory (20.2%). Relapses occurred after a median first CR duration of 16.6 months (range: 2.5-92), with 62.8% in bone marrow, 30% in CNS and 30.3% in other extramedullary sites. Phenotype at diagnosis was available for 68 pts, including 36 Early T-cell Precursor (ETP or near-ETP) (52.9%), 6 immature non-ETP (8.8%), 20 cortical (29.4%) and 6 mature phenotype (8.8%). IL7R-expression was available for 53 pts, of whom 40 were IL7R+ (75.5%) and 13 IL7R- (24.5%). Out of 50 samples with available BCL2-expression, 47 were BCL2+ (94%) and 3 BCL2- (6%). IL7R ALT were evidenced in 41 pts (48.2%), PI3K ALT in 21 pts (24.7%), RAS pathway alterations (RAS ALT) in 19 pts (22.4%) and epigenetic dysregulation in 42 pts (49.4%). Ten pts harbored TP53/ATM mutations (11.7%) . These different alterations could coexist. At relapse, 33 phenotypes were reported, showing 22 ETP (66.6%), 2 immature non-ETP (6%) and 9 cortical (27.3%). IL7R-expression was available for 26 pts, among which 21 were IL7R+ (63.6%) and 5 IL7R- (19.2%). NGS was performed in 24 patients, revealing IL7R ALT in 9 pts (37.5%), PI3K ALT in 6 pts (25%), RAS ALT in 5 pts (20.8%) and epigenetic dysregulation in 15 pts (62.5%). Nine patients had TP53 mutations (37.5%). Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%). Among these, 8 were in first salvage (32%), 10 in 2 nd (40%), and 6 in 3 rd/4 th salvage (28%). Of note, 14 patients received Ven associated with chemotherapy, including 4 Nelarabine-Ven, and 3 Ven in monotherapy. By 3 months, the cumulative incidence of response under the chosen TTO was 70.7% (95%CI:51-88) (Figure). Ten of 14 patients were in response after Aza/Ven (ORR 71.4%), 4 of 8 patients after Tofa/Ven (50%) and 2 of 2 patients treated with Tem/Erw/Ven (100%). Five patients were bridged to allogeneic stem cell transplantation. Conclusion Our results demonstrate the feasibility of the ALL-TARGET project. A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL

Recent progress in neutrino factory and muon collider research within the Muon collaboration

We describe the status of our effort to realize a first neutrino factory and the progress made in understanding the problems associated with the collection and cooling of muons towards that end. We summarize the physics that can be done with neutrino factories as well as with intense cold beams of muons. The physics potential of muon colliders is reviewed, both as Higgs Factories and compact high energy lepton colliders. The status and timescale of our research and development effort is reviewed as well as the latest designs in cooling channels including the promise of ring coolers in achieving longitudinal and transverse cooling simultaneously. We detail the efforts being made to mount an international cooling experiment to demonstrate the ionization cooling of muons

Global Climate

In 2021, both social and economic activities began to return towards the levels preceding the COVID-19 pandemic for some parts of the globe, with others still experiencing restrictions. Meanwhile, the climate has continued to respond to the ongoing increase in greenhouse gases and resulting warming. La Niña, a phenomenon which tends to depress global temperatures while changing rainfall patterns in many regions, prevailed for all but two months of the year. Despite this, 2021 was one of the six-warmest years on record as measured by global mean surface temperature with an anomaly of between +0.21° and +0.28°C above the 1991–2020 climatology. Lake surface temperatures were their highest on record during 2021. The number of warm days over land also reached a new record high. Exceptional heat waves struck the Pacific Coast of North America, leading to a new Canadian maximum temperature of 49.6°C at Lytton, British Columbia, on 29 June, breaking the previous national record by over 4°C. In Death Valley, California, the peak temperature reached 54.4°C on 9 July, equaling the temperature measured in 2020, and the highest temperature recorded anywhere on the globe since at least the 1930s. Over the Mediterranean, a provisional new European record of 48.8°C was set in Sicily on 11 August. In the atmosphere, the annual mean tropospheric temperature was among the 10 highest on record, while the stratosphere continued to cool. While La Niña was present except for June and July, likely influencing Australia’s coolest year since 2012 and wettest since 2016, other modes of variability played important roles. A negative Indian Ocean dipole event became established during July, associated with a warmer east and cooler west Indian Ocean. Northern Hemisphere winters were affected by a negative phase of the North Atlantic Oscillation at both the beginning and end of 2021. In the Southern Hemisphere, a very strong positive Southern Annular Mode (also known as the Antarctic Oscillation) contributed to New Zealand’s record warm year and to very cold temperatures over Antarctica. Land surface winds continued a slow reversal from the multi-decadal stilling, and over the ocean wind speeds were at their highest in almost a decade. La Niña conditions had a clear influence on the regional patterns of many hydrological variables. Surface specific humidity and total column water vapor over land and ocean were higher than average in almost all datasets. Relative humidity over land reached record or near-record low saturation depending on the dataset, but with mixed signals over the ocean. Satellite measurements showed that 2021 was the third cloudiest in the 19-year record. The story for precipitation was mixed, with just below-average mean precipitation falling over land and below-average mean precipitation falling over the ocean, while extreme precipitation was generally more frequent, but less intense, than average. Differences between means and extremes can be due to several factors, including using different indices, observing periods, climatological base reference periods, and levels of spatial completeness. The sharp increase in global drought area that began in mid-2019 continued in 2021, reaching a peak in August with 32% of global land area experiencing moderate or worse drought, and declining slightly thereafter. Arctic permafrost temperatures continued to rise, reaching record values at many sites, and the thickness of the layer which seasonally thaws and freezes also increased over 2020 values in a number of regions. It was the 34th-consecutive year of mass balance loss for alpine glaciers in mountainous regions, with glaciers on average 25 m thinner than in the late 1970s. And the duration of lake ice in the Northern Hemisphere was the fourth lowest in situ record dating back to 1991. The atmospheric concentrations of the major long-lived greenhouse gases, CO2, CH4, and N2O, all reached levels not seen in at least the last million years and grew at near-record rates in 2021. La Niña conditions did not appear to have any appreciable impact on their growth rates. The growth rate for CH4, of 17 ppb yr−1, was similar to that for 2020 and set yet another record, although the causes for this post-2019 acceleration are unknown presently. Overall, CO2 growth continues to dominate the increase in global radiative forcing, which increased from 3.19 to 3.23 W m−2 (watts per square meter) during the year. In 2021, stratospheric ozone did not exhibit large negative anomalies, especially near the poles, unlike 2020, where large ozone depletions appeared, mainly from dynamical effects. The positive impact of reductions in emissions of ozone depleting substances can be seen most clearly in the upper stratosphere, where such dynamical effects are less pronounced. It was the fourth-lowest fire year since global records began in 2003, though extreme regional fire activity was again seen in North America and also in Siberia; as in 2020, the effects of wildfires in these two regions led to locally large regional positive anomalies in tropospheric aerosol and carbon monoxide abundance. Vegetation is responding to the higher global mean temperatures, with the satellite-derived measures for the Northern Hemisphere for 2021 rated among the earliest starts of the growing season and the latest end of the season on record. The first bloom date for cherry trees in Kyoto, Japan, broke a 600-year record set in 1409. This year we welcome a sidebar on the global distribution of lightning, which has been recently declared an essential climate variable (ECV) by the Global Climate Observing System (GCOS). Time series and anomaly maps from many of the variables described in this chapter can be found in Plates 1.1 and 2.1. As with other chapters, many of the sections have moved from the previous 1981–2010 to the new 1991–2020 climatological reference period, in line with WMO recommendations (see Chapter 1). This is not possible for all datasets, as it is dependent on their length of record or legacy processing methods. While anomalies from the new climatology period are not so easily comparable with previous editions of this report, they more clearly highlight deviations from more recent conditions