Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways

Erratum: Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome (J. Exp. Med. (2020) 217:6 Doi:10.1084/jem.20191804)

The authors regret that in the original version of Table S1, the column for patient 12 was mistakenly duplicated in the column for patient 8. The online Table S1 PDF has been corrected. The error appears only in PDFs downloaded before June 4, 2020

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways

Nouveaux phosphorothioates dérivés de la naphthylméthylimidazoline et de la naphthyléthylimidazoline : application en radioprotection chimique

Dans ce travail, nous avons synthétisé des phosphorothioates dérivés de la 2‑(1‑naphthylméthyl)-2-imidazoline et de la 2-[1-(1-naphthyl)éthyl]-2-imidazoline afin d’évaluer, in vivo chez la souris, leur degré de protection contre les effets des rayonnements γ. Tous ces composés ont montré une activité radioprotectrice remarquable (facteur de réduction de dose compris entre 1,5 et 1,9) ce qui les classent parmi les plus actifs actuellement connus dans le domaine de la radioprotection chimique. Ces composés peuvent également présenter un intérêt dans le domaine des traitements de chimio- et de radio-thérapie

Quantitation of brain metabolites by HRMAS-NMR spectroscopy in rats exposed to sublethal irradiation.

Puropose : In the event of an acute total-body irradiation, whatever it is therapeutic or accidental, the physiopathology explaining the long-term neurological effects is unknown. We have developed a model of adult rats for which frequent behavioral assays were performed before and after a non-lethal whole-body ionizing radiation (60Co, 4,5 Gy). Learning and memory processing is an aspect of cognition involving mainly the hippocampus. We used high-resolution magic angle spinning (HRMAS) 1H NMR spectroscopy to characterize the biochemistry of four specific brain regions. The biological data for each animal will be compared to their behavioral performances, in order to underline any possible correlations. The best understanding of the physiopathological process in the Central Nervous System (CNS) will allow determining some prevention means or some enhancements for the radio-induced neurological late effects. Experimental procedures: Twenty male Wistar rats were experimented for each sample period, among which ten were gamma radiated (4.5 Gy). The cerebral structures (cortex, striata, anterior and posterior hippocampus, hypothalamus) were removed at three times: 48 hours, 8 days and 30 days after radiation. The HRMAS 1H NMR experiments were performed on a Brüker DRX Avance spectrometer at 9.4 T. Samples were spun at 4 kHz and the temperature maintained at 4°C. A spin-echo sequence with a 30ms total echo time was used. Eighteen metabolites were included in the basis. They were quantitated using the quest procedure of JMRUI software, and statistically analyzed. Moreover, another group of animals was radiated and tested in the same conditions. Then a immuno-histological study of apoptosis and neurogenesis events in the CNS was made at the same removal times. Results: NMR HRMAS results present significant differences (p<0.05) between the radiated group and the non-radiated one. GPC decreased at 48 hours post-radiation whereas Cho and PC increased, potentially with relation to a cerebral oedema. At Day-8, a decrease of Gly and Tau, and an increase in Gln, are observed in the posterior hippocampus. One month after total body irradiation, we observe an increase of GABA in cortex and striatum. Perspectives: The behavioral data, showing a significant difference in the cognitive capacities of the rats between the radiated group and the witnesses at one month, may suggest that relevant correlations are possible with biochemical and morphological modifications of the CNS. For example, the increase in GABA levels in cortex and striatum might explain the least performances of learning test

Effect of U and (137)Cs chronic contamination on dopamine and serotonin metabolism in the central nervous system of the rat

International audienceFollowing the Chernobyl accident, the most significant problem for the population of the former Soviet Union for the next 50-70 years will be chronic internal contamination by radionuclides. One of the few experiments carried out in this field reported that neurotransmitter metabolism in the central nervous system of the rat was disturbed after feeding with oats contaminated by 137 Cs for 1 month. The present study assessed the effect of chronic contamination by depleted U or 137 Cs on the metabolism of two neurotransmitters in cerebral areas of rats. Dopamine and serotonin were chosen because their metabolism has been shown to be disturbed after external irradiation, even at moderate doses. Dopamine, serotonin, and some of their catabolites were measured by high-pressure liquid chromatography coupled with an electrochemical detector in five cerebral structures of rats contaminated over a 1-month period by drinking water (40 mg U·L –1 or 6500 Bq 137 Cs·L –1 ). In the striatum, hippocampus, cerebral cortex, thalamus, and cerebellum, the dopamine, serotonin, and catabolite levels were not significantly different between the control rats and rats contaminated by U or 137 Cs. These results are not in accordance with those previously described

Chronic ingestion of uranyl nitrate perturbs acetylcholinesterase activity and monoamine metabolism in male rat brain

Recent animal studies have shown that uranium can reach the brain after chronic exposure. However, little information is available on the neurological effects of chronic long-term exposure to uranium. In the present study, the effects during 1.5, 6 and 9-month periods of chronic ingestion of uranyl nitrate (UN) in drinking water (40 mg of uranium per litre) on cholinergic acetylcholinesterase (AChE) activity and on dopaminergic and serotoninergic metabolisms were investigated in several areas of male Srague Dawley rat brains. Uranium brain accumulation and distribution was also investigated after 1.5 and 9 months. Both after 1.5, 6 and 9 months of exposure, AChE activity was unaffected in the striatum, hippocampus and frontal cortex. Nevertheless, AChE activity was transitionally perturbed in the cerebellum after 6 months of exposure. After 1.5 months of exposure, DA level increased in hypothalamus. After 6 months of exposure, a tiny but significant modification of the DAergic turnover ratio was detected in the frontal cortex. And after 9 months, UN produced a significant decrease in the 5HIAA level and the 5HTergic turn-over ratio in the frontal cortex and also a decrease in the DOPAC level and DAergic turn-over ratio in the striatum. Uranium brain accumulation was statistically significant in striatum after 1.5 months and in striatum, hippocampus and frontal cortex after 9 months of exposure. Although neurochemical changes did not always correlated with increased accumulation of uranium in specific areas, these results suggest that chronic ingestion of UN can cause chronic and progressive perturbations of physiological level of neurotransmitter systems. Considering previous reports on behavioural uranium-induced effects and the involvement of neurotransmitters in various behavioural processes, it would be crucial to determine whether these neurochemical disorders were accompanied by neurobehavioral deficits even at 40 mg of uranium per litre exposure. © 2005 Elsevier Inc. All rights reserved

A Phase III randomized study comparing a chemotherapy with cisplatin and etoposide to a etoposide regimen without cisplatin for patients with extensive small-cell lung cancer

Introduction: In a literature meta-analysis, we showed survival benefits for regimens including cisplatin [hazard ratio (HR) 0.61; 95% confidence interval (CI), 0.57-0.66] and for those including etoposide (HR 0.65; 0.61-0.69). That benefit was mainly observed when etoposide alone or in combination with cisplatin was included in the chemotherapy regimens. Our objective was to determine if chemotherapy with both drugs improves survival in comparison to a non-platinum regimen with etoposide. Methods: Extensive small-cell lung cancer patients were randomized between cisplatin-etoposide (CE) and ifosfamide + etoposide + epirubicin regimen (IVE) between 2000 and 2013. Results: 176 and 170 eligible patients were allocated to CE and IVE (315 deaths were required before analysis), respectively. Objective response rates were not significantly different: 60% with CE and 59% with IVE. No statistically significant difference in median survival and 1-year and 2-year was observed with rates of 9.6 months, 31 and 5% for CE and 10 months, 39 and 9% for IVE, respectively. HR was 0.84 (95% CI 0.68-1.05, p = 0.16). Only two prognostic factors for survival were retained in multivariate analysis: sex with HR = 0.69 (95% CI 0.49-0.97, p = 0.03) and performance status with HR = 0.53 (95% CI 0.49-0.97, p < 0.0001). After adjustment for these prognostic factors, HR for survival was 0.83 (95% CI 0.65-1.08, p = 0.17). There was more thrombopenia in the CE regimen and more leukopenia with IVE. Conclusion: Combination of CE failed to improve survival in comparison to an etoposide-containing regimen without cisplatin. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00658580?term=ELCWP+01994&rank=1, identifier NCT00658580. © 2017 Berghmans, Scherpereel, Meert, Giner, Lecomte, Lafitte, Leclercq, Paesmans and Sculier