Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

International audienc

Adalimumab therapy in pediatric Crohn’s Disease: a two-year follow-up comparing ‘top-down’ and ‘step-up’ strategies.

International audienceObjective: European Crohn’s Colitis Organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend the early use of anti-TNF biologicals in pediatric Crohn disease (CD) patients with positive predictors for poor outcome.The objective of the present study was to compare early "Top-Down" use of Adalimumab (ADA) immunomodulator/biologics-naïve patients to conventional "Step-Up" management.Methods: One hundred and twenty consecutive patients with a confirmed diagnosis of CD and treated with Adalimumab (ADA) between 2008 and 2019 were included and allocated to the ADA-Top Down (n=59) or ADA-Step Up group (n=61). The primary endpoint was prolonged steroid-/enteral nutrition-free clinical remission at 24 months, defined by a wPCDAI < 12.5. Clinical and biological data were collected at 12 and 24 months.Results: At start of ADA, disease activity was comparable between the ADA-Top Down group and the ADA-Step Up group (wPCDAI=31 ± 16 versus 31.3 ± 15.2 respectively, p=0.84). At 24 months, the remission rate was significantly higher in the ADA-Top Down group (73% versus 51%, p<0.01). After propensity score, the Top-Down strategy is still more effective than the Step-Up strategy in maintaining remission at 24 months (HR=0.36, 95%CI[0.15-0.87], p=0.02). Patients in the ADA-Top Down group were mainly on monotherapy compared to patients in the ADA-Step Up group (53/55 versus 28/55 respectively, p<0.001). Serum levels of Adalimumab were higher in the ADA-Top Down group than in the ADA-Step Up group (12.8µg/ml±4.3 versus 10.4µg/ml±3.9 respectively, p<0.01).There were no serious adverse events.Conclusion: Early use of ADA appears to be more effective in maintaining relapse-free remission at 2 years, while using it as monotherapy. These findings further favor the recommendation of early anti-TNF use in high-risk CD patients

MICROSCOPE Mission scenario, ground segment and data processing

Testing the Weak Equivalence Principle (WEP) to a precision of $10^{-15}$ requires a quantity of data that give enough confidence on the final result: ideally, the longer the measurement the better the rejection of thestatistical noise. The science sessions had a duration of 120 orbits maximum and were regularly repeated and spaced out to accommodate operational constraints but also in order to repeat the experiment in different conditions and to allow time to calibrate the instrument. Several science sessions were performed over the 2.5 year duration of the experiment. This paper aims to describe how the data have been produced on the basis of a mission scenario and a data flow process, driven by a tradeoff between the science objectives and the operational constraints. The mission was led by the Centre National d'Etudes Spatiales (CNES) which provided the satellite, the launch and the ground operations. The ground segment was distributed between CNES and Office National d'Etudes et de Recherches Aérospatiales (ONERA). CNES provided the raw data through the Centre d'Expertise de Compensation de Traînée (CECT: Drag-free expertise centre). The science was led by the Observatoire de la Côte d'Azur (OCA) and ONERA was in charge of the data process. The latter also provided the instrument and the Science Mission Centre of MICROSCOPE (CMSM)

MICROSCOPE mission scenario, ground segment and data processing

International audienceTesting the weak equivalence principle to a precision of 10$^{−15}$ requires a quantity of data that give enough confidence on the final result: ideally, the longer the measurement the better the rejection of the statistical noise. The science sessions had a duration of 120 orbits maximum and were regularly repeated and spaced out to accommodate operational constraints but also in order to repeat the experiment in different conditions and to allow time to calibrate the instrument. Several science sessions were performed over the 2.5 years duration of the experiment. This paper aims to describe how the data have been produced on the basis of a mission scenario and a data flow process, driven by a tradeoff between the science objectives and the operational constraints. The mission was led by the Centre National d’Etudes Spatiales (CNES) which provided the satellite, the launch and the ground operations. The ground segment was distributed between CNES and Office National d’Etudes et de Recherches Aérospatiales (ONERA). CNES provided the raw data through the Centre d’Expertise de Compensation de Traînée (CECT: drag-free expertise centre). The science was led by the Observatoire de la Côte d’Azur (OCA) and ONERA was in charge of the data process. The latter also provided the instrument and the Science Mission Centre of MICROSCOPE (CMSM)

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.Peer reviewe

Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER–Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome

Result of the MICROSCOPE weak equivalence principle test

International audienceThe space mission MICROSCOPE dedicated to the test of the equivalence principle (EP) operated from April 25, 2016 until the deactivation of the satellite on October 16, 2018. In this analysis we compare the free-fall accelerations (a$_{A}$ and a$_{B}$) of two test masses in terms of the Eötvös parameter . No EP violation has been detected for two test masses, made from platinum and titanium alloys, in a sequence of 19 segments lasting from 13 to 198 h down to the limit of the statistical error which is smaller than 10$^{−14}$ for η(Ti, Pt). Accumulating data from all segments leads to η(Ti, Pt) = [−1.5 ± 2.3 (stat) ± 1.5 (syst)] × 10$^{−15}$ showing no EP violation at the level of 2.7 × 10$^{−15}$ if we combine stochastic and systematic errors quadratically. This represents an improvement of almost two orders of magnitude with respect to the previous best such test performed by the Eöt-Wash group. The reliability of this limit has been verified by comparing the free falls of two test masses of the same composition (platinum) leading to a null Eötvös parameter with a statistical uncertainty of 1.1 × 10$^{−15}$