Effect of HLA DR epitope de-immunization of Factor VIII \u3ci\u3ein vitro\u3c/i\u3e and \u3ci\u3ein vivo\u3c/i\u3e

T cell-dependent development of anti-Factor VIII (FVIII) antibodies that neutralize FVIII activity is a major obstacle to replacement therapy in hemophilia A. To create a less immunogenic therapeutic protein, recombinant FVIII can be modified to reduce HLA binding of epitopes based on predicted anchoring residues. Here, we used immunoinformatic tools to identify C2 domain HLA DR epitopes and predict site-specific mutations that reduce immunogenicity. Epitope peptides corresponding to original and modified sequences were validated in HLA binding assays and in immunizations of hemophilic E16 mice, DR3 and DR4 mice and DR3 × E16 mice. Consistent with immunoinformatic predictions, original epitopes are immunogenic. Immunization with selected modified sequences lowered immunogenicity for particular peptides and revealed residual immunogenicity of incompletely de-immunized modified peptides. The stepwise approach to reduce protein immunogenicity by epitope modification illustrated here is being used to design and produce a functional full-length modified FVIII for clinical use

Gedenkwaardigheden uit de geschiedenis van Gelderland, door onuitgegevene oorkonden opgehelderd enbevestigd;

Subtitle of v. 6, pt. 2, varies slightly.Vol. 1 published by P. Nijhoff; v. 2-5, I. A. Nijhoff; v. 6, pt. 1-2, I. A. Nijhoff en zoon; v. 6, pt. 3, 's Gravenhage, M. Nijhoff.Vol. 6³ edited by L. Ed. Lenting.1. deel. De toestand van Gelderland in de eerste heift der veertiende eeuw.--2. deel. Reinald III. en Eduard, hertogen van Geire.--3. deel. Willem en Reinald IV., hertogen van Geire.--5. deel. De Bourgondische heerschappij.--6. deel, 1-3. Karel van Egmond, hertog van Geire, graaf van Zutphen.Mode of access: Internet

Genotype-dependent response to desmopressin in hemophilia A and proposal of a predictive response score

International audienceDesmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMH) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants. The study collected the evolution of FVIII levels from therapeutic intravenous DDAVP tests in 4 French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥0.50 IU.mL-1) and relative duration (based on half-life). From enrolled 439 PWMH, 327 had a hot-spot F8 variant (with ≥5 PWMH). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL-1 respectively, with FVIII recovery being 3.80 IU.ml-1 (1.15-14.75). The median FVIII half-life was 3.9h (0.7-15.9h). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMH (69%) and the median time with normalized FVIII was 3.9h (0.0-54.1h). Following the response profiles to DDAVP defined by the 4 efficacy scores, 4 groups of F8 variants were isolated then compared into survival curves with normalized FVIII (p<0.0001): “long lastingly effective” [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu) and T-stretch deletion in intron 13]; “moderately effective” [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser) and p.(Asp2150Asn)]; “moderately ineffective” [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn) and p.(Arg2178Cys)]; and “frequently ineffective” [c.-219C>T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu) and p.(Arg2326Gln)]. In view of our data, we propose indications for DDAVP-use in PWMH based on F8 variants for minor and major invasive procedures.Clinical Trial: Registration number (trial ID): NCT05628558, Trial registry: ClinicalTrials.gov (http://www.clinicaltrials.gov/), Type of Study: Multicenter stud

Enhancing quality of life and mastery of informal caregivers of high-grade glioma patients: a randomized controlled trial

High-grade gliomas (HGG) are serious primary brain tumors that may prevent the patient from functioning normally in social, emotional and cognitive respect. Often the partner's role will convert to that of informal caregiver. Consequently, they may experience significant stress and reductions in caregiver mastery, negatively affecting their health-related quality of life (HRQOL). We aimed at (1) determining factors that impact HRQOL and mastery of caregivers of HGG patients, and (2) investigate if a structured intervention consisting of psychoeducation and cognitive behavioral therapy leads to improvements in the mental component of HRQOL and mastery of caregivers. Fifty-six patient-caregiver dyads were randomly assigned to the intervention group or the care as usual group. The intervention program consisted of six one-hour sessions with a psychologist. Participants completed questionnaires concerning their perceptions of the patients' HRQOL (SF-36), neurological functioning (BN20), and cognitive functioning (MOS), and concerning their own HRQOL (SF-36) and feelings of caregiver mastery (CMS) both at baseline (i.e. before randomization) and every 2 months thereafter until 8 months later, five times in total. Patients' HRQOL and neurological functioning were found to be related to HRQOL and feelings of mastery of the informal caregiver at baseline. The intervention helped caregivers in maintaining a stable level of HRQOL and improved feelings of mastery over an 8 month period. Our findings suggest that informal caregivers can benefit from a psychological intervention as it is a helpful tool in maintaining a stable level of mental functioning and caregiver master

A compact integrated microfluidic oxygenator with high gas exchange efficiency and compatibility for long-lasting endothelialization

International audienceWe have developed and tested a novel microfluidic device for blood oxygenation, which exhibits a large surface area of gas exchange and can support long-term sustainable endothelialization of blood microcapillaries, enhancing its hemocompatibility for clinical applications. The architecture of the parallel stacking of the trilayers is based on a central injection for blood and a lateral injection/output for gas which allows significant reduction in shear stress, promoting sustainable endothelialization since cells can be maintained viable for up to 2 weeks after initial seeding in the blood microchannel network. The circular design of curved blood capillaries allows covering a maximal surface area at 4 inch wafer scale, producing high oxygen uptake and carbon dioxide release in each single unit. Since the conventional bonding process based on oxygen plasma cannot be used for surface areas larger than several cm2, a new “wet bonding” process based on soft microprinting has been developed and patented. Using this new protocol, each 4 inch trilayer unit can be sealed without a collapsed membrane even at reduced 15 μm thickness and can support a high blood flow rate. The height of the blood channels has been optimized to reduce pressure drop and enhance gas exchange at a high volumetric blood flow rate up to 15 ml min−1. The simplicity of connecting different units in the stacked architecture is demonstrated for 3- or 5-unit stacked devices that exhibit remarkable performance with low primary volume, high oxygen uptake and carbon dioxide release and high flow rate of up to 80 ml min−1

Von Willebrand factor as a biological sensor of blood flow to monitor percutaneous aortic valve interventions

Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate [PFA-CADP]), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures