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

A three-arm phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small-cell lung cancer

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

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

\uab Les linguistiques du d\ue9tachement. Actes du Colloque International de Nancy (7-9 juin 2006) \ubb. Collection SCIENCES POUR LA COMMUNICATION, Peter Lang, Berne, 2009, N\ub0 87, p. 595.

Le num\ue9ro 87 de la collection SCIENCES POUR LA COMMUNICATION est consacr\ue9 \ue0 la publication des actes du Colloque International \uab Les linguistiques du d\ue9tachement \ubb qui s\u2019est tenu \ue0 Nancy les 7-9 juin 2006. Ce colloque, dont l\u2019organisation a \ue9t\ue9 assur\ue9e par l\u2019ATILF (Analyse et Traitement Informatique de la Langue Fran\ue7aise, CNRS et Nancy-Universit\ue9s) et par le laboratoire CRISCO (Centre de Recherches Inter-langues sur la Signification en Contexte, Universit\ue9 de Caen), avait le but de r\ue9unir tous les chercheurs s\u2019int\ue9ressant aux structures \uab \ue0 d\ue9tachement \ubb, c\u2019est-\ue0-dire aux phrases dites DISLOQU\uc9ES ou SEGMENT\uc9ES (dislocation \ue0 droite ou \ue0 gauche), mais aussi \ue0 l\u2019apposition et \ue0 d\u2019autres formes de discontinuit\ue9 syntaxique. S\u2019agissant de constructions qui se r\ue9alisent, avec de fortes ressemblances, dans l\u2019ensemble des syst\ue8mes linguistiques, les organisateurs ont veill\ue9 \ue0 ce que la plus grande vari\ue9t\ue9 de langues soit repr\ue9sent\ue9e, souhaitant aboutir, au-del\ue0 des difformit\ue9s th\ue9oriques et terminologiques, \ue0 une typologie des constructions \uab \ue0 d\ue9tachement \ubb. Les actes du colloque r\ue9pertorient donc tant les \ue9tudes portant sur l\u2019\ue9crit que celles sur l\u2019oral conversationnel, et pr\ue9sentent, en m\ueame temps, un \ue9chantillonnage repr\ue9sentatif des diff\ue9rents niveaux d\u2019analyse (syntaxique, s\ue9mantique, pragmatique, prosodique), du point de vue adopt\ue9 (synchronique ou diachronique) et des mod\ue8les th\ue9oriques de r\ue9f\ue9rence. En raison de leur grand nombre, les 41 contributions seront r\ue9parties ici par grandes aires th\ue9matiques ainsi que par niveau de saillance et/ou de repr\ue9sentativit\ue9 \ue0 l\u2019int\ue9rieur de chaque aire

Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body’s principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission

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