Comparative analysis of IL6 and IL6 receptor gene polymorphisms in mastocytosis

Mastocytosis is a rare disease with reported high interleukin-6 (IL6) levels influencing disease severity. The present study investigated polymorphisms within the genes that encode IL6 and its receptor (IL6R) in relation to mastocytosis development in a case-control design. Analysis of the IL6R Asp358Ala polymorphism showed that carriers of the AA genotype had a 2.5-fold lower risk for mastocytosis than those with the AC or CC genotypes. No association with mastocytosis was found for the IL6-174G/C polymorphism, however, it may influence the effect of IL6R polymorphism. To the best of our knowledge this is the first study analysing IL6/IL6R polymorphisms in mastocytosis

A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale

OBJECTIVES: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY). METHODS: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, including mycophenolate mofetil, at a stable dose prior to randomisation is permitted in addition to weekly subcutaneous anifrolumab or placebo. Efficacy will be assessed at Week 52 via Revised-Composite Response Index in SSc (CRISS)-25 response (primary endpoint). Lung function and skin thickness will be assessed via change from baseline in forced vital capacity in patients with SSc-associated interstitial lung disease and modified Rodnan Skin Score, respectively (key secondary endpoints). CONCLUSIONS: The DAISY trial will evaluate the efficacy and safety of anifrolumab as a first-in-class treatment option for patients with both limited and diffuse cutaneous SSc and will provide insight into the contributions of type I interferon to SSc pathogenesis. Revised-CRISS-25 can account for improvement and worsening in a broad set of validated clinical measures beyond lung function and skin thickness, including clinician- and patient-reported outcomes, capturing the heterogeneity of SSc

Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation

IntroductionThe interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway.MethodIn a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001–50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33112–270 (50 ng/mL) and induced IL-8 mRNA expression measured.ResultsHEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395–270 and IL33106–270 had the greatest effect and the IL33113–270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes.ConclusionsOverall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395–270 and IL33106–270 may be more amenable to IL33/IL1RL1 targeting

A rectovaginalis sövény elsődleges adenocarcinomája az endometriosis egyidejű jelenléte nélkül

Primary adenocarcinoma of the rectovaginal septum is a rare clinical entity that arises in most of the cases from endometriosis. The authors report a successfully treated case of primary adenocarcinoma of the rectovaginal septum without associated endometriosis in a 68-year-old woman. Diagnostic and treatment modalities were reviewed by the authors emphasizing that the early diagnosis is difficult and the only curative method is primary surgical therapy

Activation of Src, Fyn and Yes non-receptor tyrosine kinases in keratinocytes expressing human papillomavirus (HPV) type 16 E7 oncoprotein

BACKGROUND: The Src family tyrosine kinases (SFK) are cellular regulatory proteins that influence cell adhesion, proliferation, invasion and survival during tumor development. Elevated activity of Src was associated with increased cell proliferation and invasivity in human papillomavirus (HPV)-associated malignancies; therefore, transduced human foreskin keratinocytes (HFK) were used to investigate whether SFK activation is a downstream effect of papillomaviral oncoproteins. Activation of ubiquitously expressed SFKs, namely Src, Yes and Fyn, was investigated in both proliferating and differentiating keratinocytes. RESULTS: In proliferating keratinocytes, Src, Yes and Fyn mRNA levels were not affected by HPV 16 E6 or E7 oncoproteins, while at the protein level as detected by western blot, the presence of both E6 and E7 resulted in substantial increase in Src and Yes expression, but did not alter the high constitutive level of Fyn. Phospo-kinase array revealed that all ubiquitously expressed SFKs are activated by phosphorylation in the presence of HPV 16 E7 oncoprotein. Keratinocyte differentiation led to increased Yes mRNA and protein levels in all transduced cell lines, while it did not influence the Src transcription but resulted in elevated Src protein level in HPV16 E7 expressing lines. CONCLUSIONS: This study revealed that HPV 16 oncoproteins upregulate Src family kinases Src and Yes via posttranscriptional mechanisms. A further effect of HPV 16 E7 oncoprotein is to enhance the activating phosphorylation of SFKs expressed in keratinocytes

Az MRI helye a sclerosis multiplex kezelés hatékonyságának megítélésében II.: mérési protokollok = The role of mri in measuring the effectivity of disease modifying treatments II

The paraclinical examinations, principally the MRI have an increasing significance in the diagnosis of multiple sclerosis. However, MRI markers also have a prominent role in monitoring of the disease-course and activity, and also in the planning of possible therapeutic changes. In accordance with previously published international guidelines, in this article we propose a protocol for the monitoring the treatment efficacy in multiple sclerosis. This could be the basis of a consensus based guideline to be implemented in Hungary

Az MRI helye a sclerosis multiplex kezelés hatékonyságának megítélésében I.: Mérési markerek = The role of mri in measuring the effect1vity of disease modifying treatments I

MRI has a significant role in the diagnosis of multiple sclerosis. The newer and newer treatment options of the disease make it necessary to monitor the effectiveness of the therapy. Besides the clinical signs (clinical relapses and progression), the different MRI parameters can also reflect the disease activity. In our current article we summarize those MRI markers, which best predict the long-term disability, based on the international standards

Biological and clinical insights from a randomised phase II study of an anti-oncostatin M monoclonal antibody in systemic sclerosis

Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of systemic sclerosis (SSc). Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. Methods This multicentre, randomised, double-blind, placebo-controlled study enrolled participants aged ≥18 years with active diffuse cutaneous SSc. Participants were randomised 3:1 (GSK2330811: placebo) in one of two sequential cohorts to receive GSK2330811 (Cohort 1: 100 mg; Cohort 2: 300 mg) or placebo subcutaneously every other week for 12 weeks. The primary end point was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory end point. Results Thirty-five participants were randomised to placebo (n = 8), GSK2330811 100 mg (n = 3) or 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. Safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events relating to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups. Conclusion Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc. Trial registration number ClinicalTrials.gov registration number: NCT03041025, EudraCT registration number: 2016-003417-95