Pharmacokinetic Enhancers (Boosters)-Escort for Drugs against Degrading Enzymes and Beyond

Pharmacokinetic enhancers (boosters) are compounds used in combination with a primary therapeutic agent (drug) and are not used for their direct effects on the disease but because they enhance or restore the activity of the primary agent. Hence, in certain cases, they represent an indispensable escort for enzyme-labile drugs. Pharmacokinetic enhancers can exert their activity on different ways. In the most common case, they inhibit enzymes such as human cytochrome P450 enzymes in the liver or other organs and, thereby, block or reduce undesired metabolism and inactivation of the primary drug. In this review, an overview will be given on the therapeutically most important classes of pharmacokinetic enhancers like beta-lactamase inhibitors, inhibitors of CYP (cytochrome P450) enzymes in HIV therapy and hepatitis C, boosters for fluoropyrimidine-type anticancer agents, compounds utilized for enabling therapy of Parkinson's disease with levodopa, and others. Inhibitors of efflux pumps in both pathogenic bacteria and tumor cells will be addresses shortly

Observations on scattering layers and thermoclines in the Baltic Sea

Records of temperature fluctuations in a thermocline show an energy peak close to the local Brunt-Väisälä frequency. This supports recent observations that short internal waves are common phenomena within the thermocline. The high rate of energy of these waves permits the conclusion that they may break and form patches of turbulence. It is assumed that these short internal waves and turbulence patches contribute to the acoustic backscattering observed from these layers

Currents and stratification in the Belt Sea and the Arkona Basin during 1962-1968

A great number of observations, mainly on temperature and current fluctuations in the Arkona Basin, have been made during the years 1962-1968 (figs. 2 and 4). Corresponding to the wind conditions over the Baltic Sea (mean value about zero, fluctuations of about 5 m sec-1), currents and stratification are extremely variable. The mean currents in fig. 7 are towards NE for the entire eastern part of the Arkona Basin, but the actual flow can have any direction (fig. 32). The current fluctuations are non-Gaussian (fig. 10). The mean stratification in the Arkona Basin underlies also great variations. Temperature fluctuations of 8°C and salinity fluctuations of 3 ‰ occur within 2 days (fig. 5). In the mean thermocline level we find also in the central part of the Arkona Basin a current towards NE (fig. 9). The current spectra of the Belt Sea and the Arkona Basin are principally of the same shape, but inertial waves do not occur in the Belt Sea (fig. 13). The mode decomposition reveals the strongest baroclinity in the period range from approximately 10h - 40h; at the inertial frequency the major baroclinic mode contains 10 times the energy of the barotropic one (fig. 28). The spectrum of the barotropic mode corresponds to the spectrum of the windstress whereas the spectra of the internal modes correspond to divergence and curl of the stress field (fig. 28). The strongest signal are the inertial currents. In general their wave length seems to be short; they consist of at least 4 internal modes and the barotropic one (fig. 37). The Reynolds stress clue to inertial waves leads to negative viscosity (fig. 40). The seiches currents are very weak compared to the inertial currents. The oscillations in the Arkona Basin seem to be short-crested and strongly influenced by Bornholm and the Rönne Bank. Towed thermistor cable records lead to the conclusion that several features of the temperature structure are of quasi-permanent character

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. METHODS: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. RESULTS: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8(+) T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. CONCLUSIONS: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion

Evaluation at the Federal University of Applied Adminstrative Sciences

Dulisch, Linssen und Reiter (2001) legten ein umfassendes Evaluationskonzept für die FH Bund vor. In den zehn Fachbereichen und im Zentralbereich der FH Bund erfolgt/e eine Diskussion, Modifikation und konkrete Anpassung an die Belange vor Ort. Dieser Prozess wurde in einer Evaluationtagung an der FH Bund im Juni 2003 gebündelt. Die Tagung zeigte, dass alle Fachbereiche und der Zentralbereich Fortschritte machen, wenn auch in unterschiedlichem Tempo. Dieser Band dokumentiert den Status Quo der Evaluation in den Fachbereichen und dem Zentralbereich und folgt damit § 6 Hochschulrahmengesetz (HRG), wonach die Arbeit der Hochschulen bewertet und das Ergebnis der Bewertung veröffentlicht werden soll. Inhaltsübersicht: - Evaluation an Fachhochschulen - Überblick - Empfehlungen des Benchmarking Clubs - Evaluationstagung der FH Bund 2003 - Zentralbereich - Allgemeine und Innere Verwaltung - Arbeitsverwaltung - Auswärtige Angelegenheiten - Bundesgrenzschutz - Bundeswehrverwaltung - Finanzen - Landwirtschaftliche Sozialversicherung - Öffentliche Sicherheit - Gesamtkonzept - Öffentliche Sicherheit - Abteilung Kriminalpolizei - Sozialversicherung - Wetterdiens

Synthesis and Antifungal Evaluation of Novel N-Alkyl Tetra- and Perhydroquinoline Derivatives

A series of novel N-alkyl tetra- and perhydroquinoline derivatives and their hydrochlorides were prepared from tetrahydro- or trans-perhydroquinoline by direct alkylation with alkyl halides and subsequent precipitation with HCl gas. The antimicrobial activity of the resulting amines was evaluated in an agar diffusion assay. The minimal inhibitory concentrations (MIC) of the active com-pounds were determined by the microdilution method. In contrast to the tetra-hydroquinolines, the perhydro analogues showed significant antifungal activity. In an assay for the detection of target enzymes in ergosterol biosynthesis, N-undecylperhydroquinoline was identified as an inhibitor of Δ8,7-isomerase