Séquence sédimentaire du secteur aval de la rivière Coppermine, Territoires du Nord-Ouest

L'étude des sédiments exposés dans 31 coupes le long du cours inférieur de la rivière Coppermine, entre les monts September et Coppermine et le golfe du Couronnement, a permis de reconstituer l'évolution postglaciaire de la région. Après le retrait des glaces, Ia mer a envahi la zone côtière déprimée par glacio-isostasie sous le niveau marin. La déglaciation a aussi permis à la rivière Coppermine de reprendre son cours vers le nord. Or, celle-ci transportait d'énormes quantités de sédiments qui lui étaient fournies d'une part par les eaux de fonte provenant des masses de glace en décrépitude et, d'autre part, par le remaniement des sédiments du lac glaciaire Coppermine. La sédimentation dans les parties relativement profondes de la mer postglaciaire est représentée par d'importants dépôts de silt et d'argile rythmés. Ces rythmites résultent d'une mise en place par des courants de turbidité. Un diamicton de plus de 30 m d'épaisseur est intercalé dans les rythmites marines. On l'interprète comme étant le résultat d'une série de coulées boueuses provoquées par la liquéfaction des varves du lac glaciaire Coppermine. Ces dépôts ont été recouverts graduellement par des sédiments de plus en plus grossiers de plage ou de delta. Il s'agit donc d'une séquence sédimentaire inverse, caractéristique d'une sédimentation dans une mer en régression. Les datations indiquent que la mer postglaciaire a envahi la région avant 10 000 ans BP.The study of 31 sections along the Coppermine River, between September and Coppermine mountains and Coronation Gulf, makes it possible to understand the postglacial history of the area. Following déglaciation, the sea invaded the depressed coastal lowlands and the Coppermine River resumed its course northward. Its high sediment load originating from the sediment-laden glacial meltwaters and the reworked Glacial Lake Coppermine deposits resulted in an important sedimentation in the postglacial sea. Sedimentation in the deeper areas of the sea left thick deposits of silt and clay rythmites. These rythmites owe their origin to turbidity currents. A 30 m-thick diamicton is interbedded with the rythmites. It is interpreted as the result of a number of debris flows generated by liquefaction of Glacial Lake Coppermine varves early in the region's postglacial history. These deposits are gradually overlaid by coarser beach or deltaic sediments, up to gravel and boulder size. This coarsening-upward sequence is typical of sedimentation in an offlap marine phase. The 14C dates suggest a minimum age of 10,000 BP for the postglacial marine phase

Regulatory T-Cell Depletion in Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is the most frequent nodal T-cell lymphoma and is characterized by a polymorphic lymph node infiltrate, various dysimmune disorders, and a poor prognosis. Regulatory T-cells (Treg) play an emerging role in the prognosis of non-Hodgkin B-cell lymphoma and mediate significant autoreactive T-cell suppression. In this report, we demonstrate that numbers of Treg are significantly decreased in AITL lymph nodes [n = 30, 91 (40–195) per high power fields] compared with follicular lymphoma [n = 19, 179 (86–355)] and reactive lymph nodes [n = 8, 186 (140–265)]. Moreover, the few Treg in lymph nodes of AITL are resting Treg (rTreg) and have a naive CD45RA+, PD1−, and ICOS− phenotype [n = 5, 57% of Treg are CD45RA+ (16–96)], in contrast to the Treg in follicular lymphomas [n = 5, 7.4% (1–13)] or reactive lymph nodes [n = 7, 18.6% (6–48)]. Interestingly, Treg depletion was not observed in AITL peripheral blood at diagnosis. Altogether, these data suggest that Treg depletion could contribute to the nodal neoplastic TFH expansion and dysimmune symptoms in AITL

Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

International audienceT cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors

Characteristics, management, and prognosis of elderly patients with COVID-19 admitted in the ICU during the first wave: insights from the COVID-ICU study

International audienceBackground: The COVID-19 pandemic is a heavy burden in terms of health care resources. Future decision-making policies require consistent data on the management and prognosis of the older patients (> 70 years old) with COVID-19 admitted in the intensive care unit (ICU). Methods: Characteristics, management, and prognosis of critically ill old patients (> 70 years) were extracted from the international prospective COVID-ICU database. A propensity score weighted-comparison evaluated the impact of intubation upon admission on Day-90 mortality. Results: The analysis included 1199 (28% of the COVID-ICU cohort) patients (median [interquartile] age 74 [72–78] years). Fifty-three percent, 31%, and 16% were 70–74, 75–79, and over 80 years old, respectively. The most frequent comorbidities were chronic hypertension (62%), diabetes (30%), and chronic respiratory disease (25%). Median Clinical Frailty Scale was 3 (2–3). Upon admission, the PaO2/FiO2 ratio was 154 (105–222). 740 (62%) patients were intubated on Day-1 and eventually 938 (78%) during their ICU stay. Overall Day-90 mortality was 46% and reached 67% among the 193 patients over 80 years old. Mortality was higher in older patients, diabetics, and those with a lower PaO2/FiO2 ratio upon admission, cardiovascular dysfunction, and a shorter time between first symptoms and ICU admission. In propensity analysis, early intubation at ICU admission was associated with a significantly higher Day-90 mortality (42% vs 28%; hazard ratio 1.68; 95% CI 1.24–2.27; p < 0·001). Conclusion: Patients over 70 years old represented more than a quarter of the COVID-19 population admitted in the participating ICUs during the first wave. Day-90 mortality was 46%, with dismal outcomes reported for patients older than 80 years or those intubated upon ICU admission

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old