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In eukaryotes, the GINS complex is essential for DNA replication and has been implicated as having a role at the replication fork. This complex consists of four paralogous GINS subunits, Psf1, Psf2, Psf3 and Sld5. Here, we identify an archaeal GINS homologue as a direct interaction partner of the MCM helicase. The core archaeal GINS complex contains two subunits that are poorly conserved homologues of the eukaryotic GINS subunits, in complex with a protein containing a domain homologous to the DNA-binding domain of bacterial RecJ. Interaction studies show that archaeal GINS interacts directly with the heterodimeric core primase. Our data suggest that GINS is important in coordinating the architecture of the replication fork and provide a mechanism to couple progression of the MCM helicase on the leading strand with priming events on the lagging strand.

Objectives: Periodic fever syndromes (PFS) are characterised by recurrent attacks of fever and localised inflammation. This study examined the diagnostic pathway and treatments at tertiary centres for FMF, TRAPS and MKD/HIDS.

Protozoan parasites belonging to the family Trypanosomatidae are characterized by an unusual pathway for the production of mRNAs via polycistronic transcription and trans-splicing of a 5′ capped mini-exon which is linked to the 3′ cleavage and polyadenylation of the upstream transcript. However, little is known of the mechanism of protein synthesis in these organisms, despite their importance as agents of a number of human diseases. Here we have investigated the role of two Trypanosoma brucei homologues of the translation initiation factor eIF4A (in the light of subsequent experiments these were named as TbEIF4AI and TbEIF4AIII). eIF4A, a DEAD-box RNA helicase, is a subunit of the translation initiation complex eIF4F which binds to the cap structure of eukaryotic mRNA and recruits the small ribosomal subunit. TbEIF4AI is a very abundant predominantly cytoplasmic protein (over 1 × 105 molecules/cell) and depletion to ∼10% of normal levels through RNA interference dramatically reduces protein synthesis one cell cycle following double-stranded RNA induction and stops cell proliferation. In contrast, TbEIF4AIII is a nuclear, moderately expressed protein (∼1–2 × 104 molecules/cell), and its depletion stops cellular proliferation after approximately four cell cycles. Ectopic expression of a dominant negative mutant of TbEIF4AI, but not of TbEIF4AIII, induced a slow growth phenotype in transfected cells. Overall, our results suggest that only TbEIF4AI is involved in protein synthesis while the properties and sequence of TbEIF4AIII indicate that it may be the orthologue of eIF4AIII, a component of the exon junction complex in mammalian cells.

BackgroundSystemic juvenile idiopathic arthritis (SJIA) is a severe autoinflammatory disease characterised by systemic features including high fevers, rash and arthritis. SJIA can impose a high physical, psychosocial, behavioral and financial burden on patients (pts) and their families.ObjectivesTo analyse the impact of the burden of SJIA by evaluating caregiver perspectives of disease burden utilising a SJIA-specific questionnaire combined with physician data about disease severity and treatment in an international, real-world study.MethodsSJIA treatment centers in France, Germany, Netherlands, UK and the US participated. Pts (aged 4–18 years) with confirmed SJIA received one of the following biologic treatments for ≥2 months: anakinra (ANA), canakinumab (CAN), or tocilizumab (TOC). SJIA burden in patients on biologics was assessed using a caregiver questionnaire and retrospective chart review. Validated measures included: Child Health Questionnaire Parent-Form 50 (CHQ-PF50), 36-Item Short-Form Health Survey (SF-36v2) and Work Productivity and Activity Impairment questionnaire: Specific Health Problem (WPAI:SHP). Caregivers completed function, treatment satisfaction and resource utilization questions.ResultsSixty-one pts enrolled from June 2015- June 2016: 12 on ANA, 25 on CAN, 24 on TOC; 46% from the US; 48% female; mean age at survey was 11.3 years. Mean age at SJIA diagnosis was 6.4 years, mean age at start of ANA, CAN, and TOC treatment was 9.9, 9.1, and 7.5 years, respectively. Caregivers were 79% female, mean age 41.2 years, and 36% reduced or stopped working due to their child's SJIA. Of the pts enrolled on CAN and TOC, 72% and 46% respectively had previously been on ANA. Baseline CHAQ, CHQ-PF50, and WPAI scores were worse in CAN and TOC than ANA pts. Mean (±SD) CHQ-PF50 physical (PhS) and psychosocial (PsS) summary scores were significantly lower in SJIA patients than a normative population (PhS: 40.0±18.2 vs. 53.0±8.8; PsS: 46.6±11.3 vs. 51.2±9.1) as was caregivers' mean SF-36v2 mental component score (46.2±10.7 vs. 50.0+10). Highest caregiver stressors were worry over long-term SJIA impact on their child (45%) and uncertainty about the future (28%).ConclusionsTreatment sequencing and patient-reported outcome measures indicate ANA is used as 1st line for less severe SJIA while CAN and TOC are used as 2nd/3rd line for severe SJIA. Caregivers expressed stress over the long-term impact of SJIA and fear for the future and had variable treatment satisfaction and resource utilisation levels.Disclosure of InterestS. Shenoi: None declared, G. Horneff Grant/research support from: Abbvie, Chugai, Novartis, Pfizer, Roche, M. Cidon: None declared, A. Ramanan: None declared, Y. Kimura Grant/research support from: Novartis, SOBI, CARRA, Inc (salary support), P. Quartier Grant/research support from: Abbvie, Novartis, Pfizer, Chugai-Roche, Consultant for: Abbvie, Novartis, Pfizer, Roche, Sobi, Speakers bureau: Abbvie, Novartis, Sobi, Roche, I. Foeldvari Speakers bureau: Novartis, Abbvie, Chugai, A. Zeft Shareholder of: ...

Background:International guidelines for hormone-receptor-positive (HR

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BackgroundHealthcare resource utilization in breast cancer varies by disease characteristics and treatment choices. However, lack of clarity in guidelines can result in varied interpretation and heterogeneous treatment management and costs. In Europe, the extent of this variability is unclear. Therefore, evaluation of chemotherapy use and costs versus hormone therapy across Europe is needed.MethodsThis retrospective chart review (N = 355) examined primarily direct costs for chemotherapy versus hormone therapy in postmenopausal women with hormone-receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer across 5 European countries (France, Germany, The Netherlands, Belgium, and Sweden).ResultsTotal direct costs across the first 3 treatment lines were approximately €10 000 to €14 000 lower for an additional line of hormone therapy-based treatment versus switching to chemotherapy-based treatment. Direct cost difference between chemotherapy-based and hormone therapy-based regimens was approximately €1900 to €2500 per month. Chemotherapy-based regimens were associated with increased resource utilization (managing side effects; concomitant targeted therapy use; and increased frequencies of hospitalizations, provider visits, and monitoring tests). The proportion of patients taking sick leave doubled after switching from hormone therapy to chemotherapy.ConclusionsThese results suggest chemotherapy is associated with increased direct costs and potentially with increased indirect costs (lower productivity of working patients) versus hormone therapy in HR+, HER2– advanced breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1762-3) contains supplementary material, which is available to authorized users.