Background: Hemophilia A results from a deficiency in factor VIII activity. Current treatment regimens require frequent dosing, owing to the short half‐life of FVIII. A recombinant FVIII–Fc fusion ...protein (rFVIIIFc) was molecularly engineered to increase the half‐life of FVIII, by 1.5–2‐fold, in several preclinical animal models and humans. Objective: To perform a biochemical and functional in vitro characterization of rFVIIIFc, with existing FVIII products as comparators.Methods: rFVIIIFc was examined by utilizing a series of structural and analytic assays, including mass spectrometry following lysyl endopeptidase or thrombin digestion. rFVIIIFc activity was determined in both one‐stage clotting (activated partial thromboplastin time) and chromogenic activity assays, in the context of the FXase complex with purified components, and in both in vitro and ex vivo rotational thromboelastometry (ROTEM) assays performed in whole blood. Results: rFVIIIFc contained the predicted primary structure and post‐translational modifications, with an FVIII moiety that was similar to other recombinant FVIII products. The von Willebrand factor‐binding and specific activity of rFVIIIFc were also found to be similar to those of other recombinant FVIII molecules. Both chromogenic and one‐stage assays of rFVIIIFc gave similar results. Ex vivo ROTEM studies demonstrated that circulating rFVIIIFc activity was prolonged in mice with hemophilia A in comparison with B‐domain‐deleted or full‐length FVIII. Clot parameters at early time points were similar to those for FVIII, whereas rFVIIIFc showed prolonged improvement of clot formation. Conclusions: rFVIIIFc maintains normal FVIII interactions with other proteins necessary for its activity, with prolonged in vivo activity, owing to fusion with the Fc region of IgG1.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of ...circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
BACKGROUND: The α and β subunits of FSH were fused to the Fc domain of IgG1 either in a single chain or a heterodimer format. These molecules were absorbed through the epithelium in lung and ...intestine by neonatal Fc receptor (FcRn)-mediated transcytosis. METHODS AND RESULTS: Single chain and heterodimer FSH–Fc were made recombinantly in Chinese hamster ovary cells. Treatment of rats with a single s.c. dose of single chain or heterodimer FSH–Fc resulted in greater stimulation of ovarian weight (20.8±3.9 and 26.9±6.1 mg respectively) compared to those receiving vehicle (12.1±1.0 mg) or an equimolar dose of recombinant human FSH (14.3±1.7 mg). Both FSH–Fc fusion proteins were absorbed after oral dosing of newborn rats with long terminal half-lives of ∼60 h, and pulmonary delivery in four cynomolgus monkeys produced maximum serum concentrations between 69 and 131 ng/ml with long terminal half-lives between 55 and 210 h. Serum inhibin levels increased after pulmonary dosing with single chain FSH–Fc (1.3- and 1.4-fold) and heterodimer FSH–Fc (5.9- and 7.1-fold) and remained elevated for >12 days after treatment with heterodimer FSH–Fc. CONCLUSIONS: We have shown that FSH–Fc fusion proteins have increased stability in blood and improved bioactivity in vivo, and that heterodimer FSH–Fc is more active in rats and monkeys than single chain FSH–Fc. These data suggest that Fc fusion proteins offer the potential for oral and pulmonary delivery of FSH.
Background
The minimally invasive direct anterior approach (MDAA) has been reported to be useful in total hip arthroplasty. The benefits of this approach may be useful for the treatment of femoral ...neck fractures. Aim of this study is to compare MDAA and postero-lateral approach (PLA) in patients treated with hip hemiarthroplasty for femoral neck fractures.
Materials and methods
Between 2013 and 2014, 109 patients underwent bipolar hip hemiarthroplasty for femoral neck fracture: 88 female and 21 male with a mean age of 88 years old. PLA was performed in 54 cases and MDAA in 55 cases.
Results
The mean surgery time was significantly lower in MDAA group (
P
= 0.001). The hemoglobin loss was significantly lower in MDAA group (
P
= 0.02). The mean postoperative pain was significantly lower in the MDAA group (
P
= 0.001). The mean hospitalization period was 2 days lower in the MDAA group but with no significant difference between the two groups (
P
= 0.09). Hip dislocation was higher in PLA cases (7.4 %) than in MDAA cases (1.8 %). Periprosthetic fracture occurred only in one case of PLA. Great trochanter fracture occurred in 1 MDAA cases, while no cases were observed in the PLA group.
Conclusions
Minimally invasive direct anterior approach for hip hemiarthroplasty in elderly people with femoral neck fracture provided significant benefit in the early postoperative period when compared to the postero-lateral approach in terms of surgery time, hemoglobin loss, postoperative pain, time of recovery and dislocation rate.
Level of evidence
Therapeutic study, level IV (case series).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
According to designer Francis A Bitonti, the full potential of technologies such as 3D printing has barely begun to be discovered. Through three of his studio's projects, he demonstrates benefits ...such as the infinite variations in product form that are achievable via the use of algorithms, as well as the carbon‐reduction prospects of locally printed customised products. He sees a future where, rather than dictating fashions, brands will become platforms for co‐creation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cyclin-dependent kinases (CDKs) are regulatory proteins of the eukaryotic cell cycle. They act after association with different cyclins, the concentrations of which vary throughout the progression of ...the cell cycle. As central mediators of cell growth, CDKs are potential targets for inhibitory molecules that would allow disruption of the cell cycle in order to evoke an antiproliferative effect and may therefore be useful as cancer therapeutics. We synthesized several inhibitory 2,6,9-trisubstituted purine derivatives and solved the crystal structure of one of these compounds, H717, in complex with human CDK2 at 2.6 Å resolution. The orientation of the C 2-p-diaminocyclohexyl portion of the inhibitor is strikingly different from those of similar moieties in other related inhibitor complexes. The N 9-cyclopentyl ring fully occupies a space in the enzyme which is otherwise empty, while the C 6-N-aminobenzyl substituent points out of the ATP-binding site. The structure provides a basis for the further development of more potent inhibitory drugs.
Skeletal surgery for airway issues Bitonti, David A
Oral and maxillofacial surgery clinics of North America,
08/2007, Volume:
19, Issue:
3
Journal Article
Peer reviewed
Skeletal surgeries, specifically orthognathic procedures are an integral part of the treatment regimen for patients with airway issues. As evaluation mechanisms for, research into, and treatment ...options for, patients with airway issues have become refined, so have the techniques used to treat them become more focused and less prescriptive. The diagnosis for the severity of the airway compromise has also undergone an evolutionary change, with the diagnostic criteria becoming more restrictive and the equipment for diagnosing them more sophisticated.
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