Zur operativen Behandlung der Strahlenperikarditis durch subtotale Perikardresektion

Ohne Zusammenfassung     

Biliary excretion of iodipamide and iodoxamate in dogs with hepatic dysfunction induced by oral administration of dimethylnitrosamine

Iodipamide and iodoxamate were compared in equimolar clinical dosages in five cholecystectomized chronic bile fistula dogs in which hepatic dysfunction was produced by oral administration of a total dose of 480 and 960 microliters dimethylnitrosamine (DMNA), respectively. After both DMNA dosages, the peak biliary excretion rate for iodoxamate was significantly higher than for iodipamide (p less than 0.01). The peak bile iodine concentration was not significantly different for the two agents (480 microliter DMNA: p less than 0.1; 960 microliter DMNA: p = 0.07). On the basis of this investigation, it is suggested that iodoxamate should not significantly improve the opacification of the biliary system in patients with hepatic dysfunction.     

Immune recovery after conventional and non-myeloablative allogeneic stem cell transplantation

The immune recovery of 66 patients undergoing allogeneic stem cell transplantation with either conventional or non-myeloablative conditioning regimen was studied. Infections post-transplant were enumerated and quantitative immunoglobuilins (IgG, IgA, IgM) and lymphocyte sub-sets 3, 6 and 12 months post-transplant were measured. A significant difference was found in the immunologic recovery of non-myeloablative and conventional ASCT in the patient population. The T-helper cell reconstitution was significantly faster after NMA than conventional transplantation and the recovery of B cells was faster after conventional transplantation. Regarding immunoglobulin levels, a faster recovery of IgM levels after NMA-ASCT and a delayed recovery of IgA levels was observed in both groups. These were accompanied by a significant difference in the frequency and severity of infectious episodes.     

Strategies for the design of potent and selective kinase inhibitors

The characterisation of the human kinome in recent years has resulted in the emergence of numerous kinase drug targets in a variety of therapeutic areas. Through the elucidation of the sequence and structural composition of kinase active sites, coupled with the solution of numerous ATP competitive ligand complex structures, significant advances have been made in developing inhibitors that are highly selective. This has shown to be the case not only for kinases that are divergent in primary structure, but also for isoforms with highly conserved structure and ATP binding sites. Here we review the methods employed in the generation of selective inhibitors and describe several successful examples of the design of highly potent and selective kinase ATP competitive ligands. We also describe examples where an alternate approach to selectivity was used. These include the use of small molecules to sequester kinases in inactive conformations, and to block phospho-transferase activity by preventing substrate docking and recruitment. Substrate recruitment sites are promising from a structure based design perspective as they contain features unique to individual protein kinases.     

Recent progress in plantibody technology

Antibodies are an important class of proteins that can be used for the prevention, treatment and diagnosis of many diseases. Consequently, there is an intense and growing demand for recombinant antibodies, placing immense pressure on current production capacity which is based largely on microbial cultures and mammalian cells. Alternative systems for cost effective antibody production would be very welcome, and plants are now gaining widespread acceptance as green bioreactors with advantages in terms of cost, scalability and safety. Several plant-produced antibodies (plantibodies) are undergoing clinical trials and the first commercial approval could be only a few years away. The performance of the first generation of products has been very encouraging so far. In terms of product authenticity, differences in glycosylation between plantibodies and their mammalian counterparts have been defined, and the scientific evaluation of any possible consequences is underway. Ongoing studies are addressing the remaining biochemical constraints, and aim to further improve product yields, homogeneity and authenticity, particularly where the antibody is intended for injection into human patients. A remaining practical challenge is the implementation of large-scale production and processing under good manufacturing practice conditions that are yet to be endorsed by regulatory bodies. The current regulatory uncertainty and the associated costs represent an entry barrier for the pharmaceutical industry. However, the favourable properties of plants are likely to make the plant systems a useful alternative for small, medium and large scale production throughout the development of new antibody-based pharmaceuticals.     

Endocytosis and cationic cell-penetrating peptides--a merger of concepts and methods

With the identification of fixation as a major source of artefacts in the cell biological research on cell-penetrating peptides (CPPs), the past two years have witnessed a dramatic development in the CPP field. At least for some of these molecules, endocytosis is now considered to be the major if not the exclusive route of cellular import. However, endocytosis comprises a variety of different pathways with very different implications for the delivery of bioactive molecules to the cytoplasm and nucleus. The endocytosis of CPPs is governed by complex mechanisms similar to those responsible for the internalization of other molecules. Therefore the investigation of uptake and intracellular trafficking of CPPs can benefit enormously from the understanding of the endocytic machinery as well as from the tools that have already been developed for the analysis of endocytosis. This review will introduce aspects of endocytosis relevant to the analysis of CPPs. In addition to the methods, that have already been used for the analysis of CPP trafficking, we will also present other tools and approaches which can be helpful for the research of CPP uptake. Furthermore this review will analyze and summarize recent data providing new insights in endocytosis and intracellular trafficking of CPPs.