Monopyrrolische VorHiufer fur die Synthese des Uroporp hyrinogen -octani trils

Syntheses of the pre-uroporphinoid monopyrrolic derivatives porphobilinogen dinitrile, deaminomethyl-porphobilinogen dinitrile and 5-deaminomethyl-2-hydroxymethyl-porphobilinogen dinitrile make multiple use of the crystalline Mannich salt dimethyl- -methylidene-iminiumjodide as areagent for the introduction of cyanomethyl and ,B-cyanoethylside chains at the ,B-positionof the pyrrol nucleus. The paper is the first in a series of reports on the chemistry of uroporphyrinogen octanitrile

Development of a Human Cytomegalovirus (HCMV)-Based Therapeutic Cancer Vaccine Uncovers a Previously Unsuspected Viral Block of MHC Class I Antigen Presentation

Human cytomegalovirus (HCMV) induces a uniquely high frequency of virus-specific effector/memory CD8+ T-cells, a phenomenon termed “memory inflation”. Thus, HCMV-based vaccines are particularly interesting in order to stimulate a sustained and strong cellular immune response against cancer. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high lethality and inevitable relapse. The current standard treatment does not significantly improve the desperate situation underlining the urgent need to develop novel approaches. Although HCMV is highly fastidious with regard to species and cell type, GBM cell lines are susceptible to HCMV. In order to generate HCMV-based therapeutic vaccine candidates, we deleted all HCMV-encoded proteins (immunoevasins) that interfere with MHC class I presentation. The aim being to use the viral vector as an adjuvant for presentation of endogenous tumor antigens, the presentation of high levels of vector-encoded neoantigens and finally the repurposing of bystander HCMV-specific CD8+ T cells to fight the tumor. As neoantigen, we exemplarily used the E6 and E7 proteins of human papillomavirus type 16 (HPV-16) as a non-transforming fusion protein (E6/E7) that covers all relevant antigenic peptides. Surprisingly, GBM cells infected with E6/E7-expressing HCMV-vectors failed to stimulate E6-specific T cells despite high level expression of E6/E7 protein. Further experiments revealed that MHC class I presentation of E6/E7 is impaired by the HCMV-vector although it lacks all known immunoevasins. We also generated HCMV-based vectors that express E6-derived peptide fused to HCMV proteins. GBM cells infected with these vectors efficiently stimulated E6-specific T cells. Thus, fusion of antigenic sequences to HCMV proteins is required for efficient presentation via MHC class I molecules during infection. Taken together, these results provide the preclinical basis for development of HCMV-based vaccines and also reveal a novel HCMV-encoded block of MHC class I presentation

Varicellovirus UL49.5 Proteins Differentially Affect the Function of the Transporter Associated with Antigen Processing, TAP

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms

Identification of Spin Diffusion Pathways in Isotopically Labeled Biomolecules

One-dimensional NOE expts. applicable to labeled macromols. are presented which allow the manipulation of specific spin diffusion pathways and thus unambiguously identify clandestine spins through which the direct NOE is mediated. A treatment of spin diffusion using av. Liouvillian theory is shown to describe adequately these phenomena. Expts. are carried out on an 15N-labeled sample of human ubiquitin. (c) 1999 Academic Press. [on SciFinder (R)

Biological and environmental exposure monitoring of volatile organic compounds among nail technicians in the Greater Boston area

Nail technicians are exposed to volatile organic compounds (VOCs) from nail products, but no studies have previously measured VOC biomarkers for these workers. This study of 10 nail technicians aimed to identify VOCs in nail salons and explore relationships between air concentrations and biomarkers. Personal and area air samples were collected using thermal desorption tubes during a work shift and analyzed using gas chromatography/mass spectrometry (GC/MS) for 71 VOCs. Whole blood samples were collected pre-shift and post-shift, and analyzed using GC/MS for 43 VOCs. Ventilation rates were determined using continuous CO2 measurements. Predominant air VOC levels were ethyl methacrylate (median 240 µg/m3), methyl methacrylate (median 205 µg/m3), toluene (median 100 µg/m3), and ethyl acetate (median 639 µg/m3). Blood levels were significantly higher post-shift than pre-shift for toluene (median pre-shift 0.158 µg/L and post-shift 0.360 µg/L) and ethyl acetate (median pre-shift \u3c0.158 µg/L and post-shift 0.510 µg/L); methacrylates were not measured in blood because of their instability. Based on VOCs measured in these seven nail salons, we estimated that emissions from Greater Boston area nail salons may contribute to ambient VOCs. Ventilation rates did not always meet the ASHRAE guideline for nail salons. There is a need for changes in nail product formulation and better ventilation to reduce VOC occupational exposures

Conflicts in Water Resources Planning

Center for Water and the Environmen

Objective consensus from decision trees

BackgroundConsensus-based approaches provide an alternative to evidence-based decision making, especially in situations where high-level evidence is limited. Our aim was to demonstrate a novel source of information, objective consensus based on recommendations in decision tree format from multiple sources.MethodsBased on nine sample recommendations in decision tree format a representative analysis was performed. The most common (mode) recommendations for each eventuality (each permutation of parameters) were determined. The same procedure was applied to real clinical recommendations for primary radiotherapy for prostate cancer. Data was collected from 16 radiation oncology centres, converted into decision tree format and analyzed in order to determine the objective consensus.ResultsBased on information from multiple sources in decision tree format, treatment recommendations can be assessed for every parameter combination. An objective consensus can be determined by means of mode recommendations without compromise or confrontation among the parties. In the clinical example involving prostate cancer therapy, three parameters were used with two cut-off values each (Gleason score, PSA, T-stage) resulting in a total of 27 possible combinations per decision tree. Despite significant variations among the recommendations, a mode recommendation could be found for specific combinations of parameters.ConclusionRecommendations represented as decision trees can serve as a basis for objective consensus among multiple parties

[18F]fludeoxyglucose PET/CT in small-cell lung cancer:Analysis of the CONVERT randomized controlled trial

At 00:30 (local time) on the 10th September 2003 a joint and foliation defined wedge of material with an estimated volume of 7–12×106 m3 slid into the narrow Tsatichhu River Valley, in Jarrey Geog, Lhuentse, eastern Bhutan. The Tsatichhu River, a north–easterly flowing tributary of the Kurichuu River, was completely blocked by the landslide. During its movement, the landslide transitioned into a rock avalanche that travelled 580 m across the valley before colliding with the opposite valley wall. The flow then moved down valley, travelling a total distance of some 700 m. The rock avalanche was accompanied by an intense wind blast that caused substantial damage to the heavily forested valley slopes. The resulting geomorphologically-typical rock-avalanche dam deposit created a dam that impounded a water volume of 4–7×106 m3 at lake full level. This lake was released by catastrophic collapse of the landslide, which occurred at 16:20 (local time) on 10th July 2004, after reported smaller failures of the saturated downstream face. The dam failure released a flood wave that had a peak discharge of 5900 m3 s−1 at the Kurichhu Hydropower Plant 35 km downstream