DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

C1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface-gC1qR and cC1qR-lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca(2+) and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca(2+)-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN-mediated induction of cell-signaling pathways.     

Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: proceedings from the 6th International Post-ASH Symposium

Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.     

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX,in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double‐blind, non‐inferiority, cross‐over study conducted in participants aged ≥12 years weighing ≥40 kg, with severe or moderately severe haemophilia B (FIX activity ≤2 IU dL ^?1). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4–18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8–59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg^?1 or nonacog alfa. The lower limit of the one‐sided 95% confidence interval for the ratio of AUC_0‐t and AUC_0‐∞ (IB1001/nonacog alfa) was 0.90, establishing non‐inferiority. Terminal phase half‐lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non‐inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.     

Femtosecond laser-assisted implantation of corneal stroma lenticule for keratoconus

International Ophthalmology - To review recent progress, challenges, and future perspectives of stromal keratophakia for the treatment of advanced keratoconus. We systematically reviewed the...     

Adult-onset mitochondrial movement disorders: a national picture from the Italian Network

Journal of Neurology - Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. Based on the database of the...