AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

BACKGROUND: Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. METHODS: We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. RESULTS: Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. CONCLUSIONS: The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).BioMarin Pharmaceutical

A review of composite product data interoperability and product life-cycle management challenges in the composites industry

A review of composite product data interoperability and product life-cycle management challenges is presented, which addresses “Product Life-cycle Management”, developments in materials. The urgent need for this is illustrated by the life-cycle management issues faced in modern military aircraft, where in-service failure of composite parts is a problem, not just in terms of engineering understanding, but also in terms of the process for managing and maintaining the fleet. A demonstration of the use of ISO 10303-235 for a range of through-life composite product data is reported. The standardization of the digital representation of data can help businesses to automate data processing. With the development of new materials, the requirements for data information models for materials properties are evolving, and standardization drives transparency, improves the efficiency of data analysis, and enhances data accuracy. Current developments in Information Technology, such as big data analytics methodologies, have the potential to be highly transformative

Schaffung von Grundlagen zur stofflichen Verwertung von Miscanthus sinensis. T. 1

Renewable feedstocks like Miscanthus sinensis are more and more becoming the most viable solution for the conservation of the environment and constitute the basic requisite for the continued existence of a healthy climate and life. Already within a relatively brief and foreseeable period of time, the constant consumption of fossil energy sources, combined at present with irreversible structural changes, causes serious problems for the continuance of living conditions. By current standards, renewable feedstocks offer the best solution to this problem. - Processed into intermediate and end-use products, they form a closed biological cycle. Carbon dioxide required for plant growth is taken from the atmosphere and converted into hydrocarbon-hydrogen structures, a process causing the formation of oxygen. Composting or combustion results again in the release of carbon dioxide. Fast-growing varieties with effective C4-photosynthesis like Miscanthus sinensis seem particularly suited. Consequently, the utilization of renewable feedstocks does not aggravate atmospheric carbon dioxide pollution and thus is the most urgent demand of our time. (EF)Nachwachsende Rohstoffe wie Miscanthus sinensis sind in zunehmendem Masse die brauchbarste Loesung fuer die Schonung der Umwelt und die existentielle Basis fuer das Fortbestehen eines gesunden Klimas und des Lebens. Der staendige Verbrauch fossiler Rohstoffe in Verbindung mit derzeit irreversibler Strukturwandlung bringt bereits in relativ kurzer und ueberschaubarer Zeit schwere Probleme bei der Reproduktion der Lebensbedingungen. Nachwachsende Rohstoffe bieten nach dem derzeitigen Erkenntnisstand den optimalen Ausweg aus diesem Problem. Sie bieten bei entsprechender Verarbeitung zu Zwischen- und Endprodukten die Moeglichkeit eines biologisch geschlossenen Kreislaufes. Das beim Pflanzenwachstum aus der Atmosphaere entzogene Kohlendioxid wird unter Freisetzung von Sauerstoff in Kohlenstoff- Wasserstoff-Strukturen umgewandelt und bei der Kompostierung oder Verbrennung wieder freigesetzt. Dabei erscheinen schnellwachsende Arten mit effektiver C4-Photosynthese, wie Miscanthus sinensis, besonders geeignet. Die stoffliche Nutzung belastet demzufolge nicht die Kohlendioxyd-Bilanz der Atmosphaere und ist somit gleichzeitig die dringendste Forderung der heutigen Zeit. (EF)SIGLEAvailable from TIB Hannover: F95B91+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany); Bundesministerium fuer Ernaehrung, Landwirtschaft und Forsten, Bonn (Germany)DEGerman

TSPO PET for glioma imaging using the novel ligand 18F-GE-180: first results in patients with glioblastoma

Objective The 18-kDa mitochondrial translocator protein (TSPO) was reported to be upregulated in gliomas. F-18-GE-180 is a novel 3rd generation TSPO receptor ligand with improved target-to-background contrast compared to previous tracers. In this pilot study, we compared PET imaging with F-18-GE-180 and MRI of patients with untreated and recurrent pretreated glioblastoma. Methods Eleven patients with histologically confirmed IDH wildtype gliomas (10 glioblastomas, 1 anaplastic astrocytoma) underwent F-18-GE-180 PET at initial diagnosis or recurrence. The PET parameters mean background uptake (SUVBG), maximal tumour-to-background ratio (TBRmax) and PET volume using different thresholds (SUVBG x 1.6, 1.8 and 2.0) were evaluated in the 60-80 min p.i. summation images. The different PET volumes were compared to the contrast-enhancing tumour volume on MRI. Results All gliomas were positive on F-18-GE-180 PET and were depicted with extraordinarily high tumour-to-background contrast (median SUVBG 0.47 (0.37-0.93), TBRmax 6.61 (3.88-9.07)). F-18-GE-180 uptake could be found even in areas without contrast enhancement on MRI, leading to significantly larger PET volumes than MRI-based volumes (median 90.5, 74.5, and 63.8 mL vs. 31.0 mL; p = 0.003, 0.004, 0.013). In percentage difference, the PET volumes were on average 179%, 135%, and 90% larger than the respective MRI volumes. The median spatial volumetric correlation (Sorensen-Dice coefficient) of PET volumes and MRI volumes prior to radiotherapy was 0.48, 0.54, and 0.58. Conclusion F-18-GE-180 PET provides a remarkably high tumour-to-background contrast in untreated and pretreated glioblastoma and shows tracer uptake even beyond contrast enhancement on MRI. To what extent F-18-GE-180 uptake reflects the tumour extent of human gliomas and inflammatory cells remains to be evaluated in future prospective studies with guided stereotactic biopsies and correlation of histopathological results

TSPO PET, tumour grading and molecular genetics in histologically verified glioma: a correlative 18F-GE-180 PET study

Background The 18-kDa translocator protein (TSPO) is overexpressed in brain tumours and represents an interesting target for glioma imaging. F-18-GE-180, a novel TSPO ligand, has shown improved binding affinity and a high target-to-background contrast in patients with glioblastoma. However, the association of uptake characteristics on TSPO PET using F-18-GE-180 with the histological WHO grade and molecular genetic features so far remains unknown and was evaluated in the current study. Methods Fifty-eight patients with histologically validated glioma at initial diagnosis or recurrence were included. All patients underwent F-18-GE-180 PET, and the maximal and mean tumour-to-background ratios (TBRmax, TBRmean) as well as the PET volume were assessed. On MRI, presence/absence of contrast enhancement was evaluated. Imaging characteristics were correlated with neuropathological parameters (i.e. WHO grade, isocitrate dehydrogenase (IDH) mutation, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and telomerase reverse transcriptase (TERT) promoter mutation). Results Six of 58 patients presented with WHO grade II, 16/58 grade III and 36/58 grade IV gliomas. An (IDH) mutation was found in 19/58 cases, and 39/58 were classified as IDH-wild type. High F-18-GE-180-uptake was observed in all but 4 cases (being WHO grade II glioma, IDH-mutant). A high association of F-18-GE-180-uptake and WHO grades was seen: WHO grade IV gliomas showed the highest uptake intensity compared with grades III and II gliomas (median TBRmax 5.15 (2.59-8.95) vs. 3.63 (1.85-7.64) vs. 1.63 (1.50-3.43), p 0.05 each). Conclusion Uptake characteristics on F-18-GE-180 PET are highly associated with the histological WHO grades, with the highest F-18-GE-180 uptake in WHO grade IV glioblastomas and a PET-positive rate of 100% among the investigated high-grade gliomas. Conversely, all TSPO-negative cases were WHO grade II gliomas. The observed association of F-18-GE-180 uptake and the IDH mutational status seems to be related to the high inter-correlation of the IDH mutational status and the WHO grades