SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection

Évaluation d’une dosimétrie in vivo de transit utilisant l’imageur portal et comparaison avec les mesures par diodes

International audiencePurposeIn vivo dosimetry transit using portal imaging is a promising approach for quality assurance in radiotherapy. A comparative evaluation was conducted between a commercial solution, EPIgray® and an in vivo dosimetry control reference using semiconductors diodes.Material and methodsThe performance of the two in vivo dosimetry methods was assessed. The primary endpoint was the dose deviation between the reconstructed dose at the prescription point and the measured dose using the ionization chamber in phantoms or the calculated predictive dose by the treatment planning system with patients. The deviation threshold was set to ±5%. In total, 107 patients were prospectively included and treated with 3D-conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) techniques for tumours of the brain, chest and head and neck.ResultsThe dosimetric accuracy of EPIgray® in phantom were comparable to diodes in terms of repeatability (0.11%), reproducibility (0.29–0.51%) with a mean dose deviation of 0.17% (SD: 1.11). The rates of radiotherapy sessions out of the tolerance for the brain (3D-CRT and IMRT), thorax (3D-CRT) and the head and neck (IMRT) were respectively 0%, 9.6% and 5.3% with a mean dose deviation ranging between 0.49% and 1.53%. The mean of dose deviation between three consecutive sessions with EPIgray® validates 99.1% of treatments.ConclusionThe performance of EPIgray® in in vivo dosimetry is consistent with the recommendations of the European Society for Radiotherapy and Oncology (ESTRO) and equivalent to semiconductor diodes for 3D-CRT. It also allows adequate control for IMRT, which is technically difficult to perform with the diodes.Objectifs de l’étudeLa dosimétrie in vivo de transit utilisant l’imageur portal est une approche prometteuse pour l’assurance qualité en radiothérapie. Une évaluation comparative a été menée entre une solution commerciale, EPIgray® et un contrôle de dosimétrie in vivo de référence utilisant des diodes à semi-conducteurs.Matériel et méthodesLes performances des deux méthodes de dosimétrie in vivo ont été évaluées. Le critère principal était l’écart de dose au point de prescription par rapport aux mesures de la chambre d’ionisation sur fantôme ou par rapport à la dose prévisionnelle calculée par le système de planification de traitement avec les patients. Le seuil de tolérance de l’écart de dose était défini à ±5 %. Au total, 107 patients traités par irradiation conformationnelle tridimensionnelle avec ou sans modulation d’intensité pour des tumeurs de l’encéphale, du thorax, de la tête et du cou ont été inclus prospectivement.RésultatsLa précision dosimétrique d’EPIgray® sur fantôme était comparable à celle des mesures par diodes en termes de répétabilité (0,11 %) et de reproductibilité (0,29–0,51 %), avec un écart de dose moyen de 0,17 % (écart-type : 1,11). Les taux de séances hors tolérances pour l’encéphale (irradiation conformationnelle tridimensionnelle avec ou sans modulation d’intensité), le thorax (irradiation conformationnelle tridimensionnelle) et la tête et le cou (irradiation conformationnelle avec modulation d’intensité) étaient respectivement de 0 % ; 9,6 % et 5,3 % avec un écart de dose moyen entre 0,49 % et 1,53 %. La moyenne de l’écart de dose sur trois séances consécutives avec EPIgray® permettait de valider 99,1 % des traitements.ConclusionLes performances d’EPIgray® en dosimétrie in vivo sont compatibles avec les recommandations de l’European Society for Radiotherapy and Oncology (ESTRO) et équivalentes à celles des diodes à semi-conducteur pour l’irradiation conformationnelle tridimensionnelle. Elle permet un contrôle satisfaisant des irradiations conformationnelles avec modulation d’intensité, techniquement difficiles à réaliser avec les diodes

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy

Aims: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (C meanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods: Individual exposures (C meanIND ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan–Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. Results: Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing C meanIND (hazard ratio = 1.74 and 0.394 at 5 th and 95 th percentile compared to median C meanIND ) and was inferior in patients with high baseline tumour size and B symptoms. Conclusions: It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with &gt;1 dose level of G could help resolve this uncertainty. </p

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection