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  • 1
    Abstract: The immunodominant MART-1(26(27)-35) epitope, liberated from the differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (MART-1/Melan-A), has been frequently targeted in melanoma immunotherapy, but with limited clinical success. Previous studies suggested that this is in part due to an insufficient peptide supply and epitope presentation, since proteasomes containing the immunosubunits beta5i/LMP7 (LMP, low molecular weight protein) or beta1i/LMP2 and beta5i/LMP7 interfere with MART-1(26-35) epitope generation in tumor cells. Here, we demonstrate that in addition the IFN-gamma-inducible proteasome subunit beta2i/MECL-1 (multicatalytic endopeptidase complex-like 1), proteasome activator 28 (PA28), and ER-resident aminopeptidase 1 (ERAP1) impair MART-1(26-35) epitope generation. beta2i/MECL-1 and PA28 negatively affect C- and N-terminal cleavage and therefore epitope liberation from the proteasome, whereas ERAP1 destroys the MART-1(26-35) epitope by overtrimming activity. Constitutive expression of PA28 and ERAP1 in melanoma cells indicate that both interfere with MART-1(26-35) epitope generation even in the absence of IFN-gamma. In summary, our results provide first evidence that activities of different antigen-processing components contribute to an inefficient MART-1(26-35) epitope presentation, suggesting the tumor cell's proteolytic machinery might have an important impact on the outcome of epitope-specific immunotherapies.
    Type of Publication: Journal article published
    PubMed ID: 26399368
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  • 2
    Abstract: Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-gamma-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-gamma-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-gamma-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.
    Type of Publication: Journal article published
    PubMed ID: 27143649
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  • 3
    ISSN: 1432-0738
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zusammenfassung Es wird über einen speziellen Analysengang zum Nachweis der Phenothiazinderivate unter toxikologischen Gesichtspunkten berichtet. Versuche an Reinsubstanzen und an Urinextrakten von Patienten, die unter Phenothiazinmedikation standen, wurden durchgeführt. Die besonderen Löslichkeitsverhältnisse der Phenothiazinderivate führten zur Anwendung eines speziellen Extraktionsmittels, bestehend aus einer Mischung von Hexan, Benzol und Äther zu jeweils gleichen Teilen. Es wurde aufsteigend chromatographiert auf gepufferten Papieren mit den PH-Werten 3,5, 6,0 und 7,5 unter Verwendung von Butanol-Puffergemisch als mobile Phase. Der Nachweis auf dem Chromatogramm geschah mit Palladiumchlorid als Sprühreagens, das die Phenothiazinderivate spezifisch anfärbt und eine Unterscheidung von den basischen Suchtmitteln ermöglicht. Spektrophotometrisch weisen die Phenothiazinkörper eine charakteristische Absorptionskurve im UV auf, wobei ausgeprägte Maxima bei 300 mμ und bei 250 mμ sowie ein Minimum bei 280 mμ auftreten. Eine weitere typische Extinktionskurve wird nach Bromierung der Substanzen erhalten. Zur quantitativen Bestimmung wird die Differenz zwischen dem Maximum bei 250 mμ und dem Minimum bei 280 mμ benutzt. Die untere Erfassungsgrenze für die Phenothiazinderivate liegt dabei bei 1γ. Aus Urinextrakten konnte der spektrophotometrische Nachweis nach papierchromatographischer Vorreinigung eindeutig durchgeführt werden.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 16 (1957), S. 401-407 
    ISSN: 1432-0738
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zusammenfassung Im Mageninhalt von E 605-Suicidfällen, der bei Zimmertemperatur aufbewahrt worden war, ließ sich noch nach 8 Monaten der Wirkstoff des E 605 mit Hilfe der spezifischen UV-Absorptionskurve nachweisen. Bei Versuchen mit kleineren zugesetzten Mengen an E 605 zu Mageninhalt, war die Nachweisbarkeitsdauer mit der beschriebenen Methode kürzer. Nach dreiwöchigem Erdgrab konnte im Mageninhalt von Kaninchen der Wirkstoff noch durch den Kurvenverlauf nachgewiesen werden. Die Zersetzung der Mageninhaltsstoffe bei mehrmonatigem Stehen bei Zimmertemperatur hat keinen wesentlichen Einfluß auf die Nachweisbarkeitsdauer mit Hilfe der Messung der Extinktionskurven des Esters wie des p-Nitrophenol. In den Fällen, bei denen der spezifische Kurvenverlauf der Extinktion für die zu ermittelnden Substanzen nicht mehr zu erhalten war, konnte p-Nitrophenol nach einer einfachen Anreicherungsmethode noch nachgewiesen werden.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0738
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary While pipetting, a lady-technician sucked up approximately 1.5 ml of a10% solution of sodium-azide (NaN3) and accidently swallowed the solution. After 5 minutes breathlessness and high pulse-rate were noticed, a quarter of an hour later nausea and vomiting with distracting headaches, restlessness and diarrhea became manifested. A remarkable polydipsia was noted and the clinical evaluation showed T-wove-changes of the electrocardiogram and leucocytosis with deviation to the left in the differential blood count. 10 days later the patient had not completely recovered and showed an increase of perspiration and slight numbness. The clinical identification of swallowed sodium-azide can easily be identified in the filtered gastric juice by adding a few drops of diluted ferric(III)-chloride-solution to the filtered gastric juice. A deep red colour will be obtained [ferric-azide Fe(N3)3]. The test is highly sensitive.
    Notes: Zusammenfassung Beim Pipettieren sog eine med.-techn. Assistentin etwa 1,5 ml einer 10%igen Natriumazidlösung auf und schluckte die Lösung. Nach 5min traten Atemnot und Pulsbeschleunigung auf, nach 15 min übelkeit, Erbrechen, heftiger Kopfschmerz, Unruhe und Diarrhoe. AuffÄllig war eine Polydipsie, klinisch bestanden Erregungsrückbildungsstörungen im Elektrokardiogramm und Leukocytose mit Linksverschiebung im Differentialblutbild. Noch nach 10 Tagen bestand Leistungsinsuffizienz mit deutlicher Schwei\neigung bei Belastung und leichte Benommenheit. Der chemische Nachweis von eingenommenem Natriumazid gelingt leicht und mit gro\er Empfindlichkeit im filtrierten Magensaft durch Bildung von tiefrotem Eisenazid [Fe(N3)3] nach Zugabe einiger Tropfen verdünnter Eisen(III)-chloridlösung.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Cellular cation was localized with K-pyroantimonate osmium fixation in whole fetal mouse metatarsal bones and in deliberately mechanically damaged specimens. X-ray microprobe analysis of ultrathin sections showed a positive correlation between the concentration of Ca (and Sb) and the amount of electron-dense precipitate. In non-damaged osteoblasts and growth-plate chondrocytes dense precipitate had accumulated along the plasmalemma and the mitochondrial membranes, whereas damaged cells showed the precipitate on round granules in the mitochondrial matrix but not on membranes. Intermediate stages between these two patterns were also found. In a non-calcifying tissue such as liver no membrane-bound precipitate was found in intact cells. However, damaged liver cells showed precipitate-containing mitochondrial granules similar to those in damaged bone cells, but only after incubation of the damaged tissue for l h in a Ca-containing balanced salt solution. Freezing of fresh whole bones in liquid N2 before fixation in K-pyroantimonate osmium did not change the precipitate pattern in the damaged cells, but in intact cells it produced a random distribution of precipitate unrelated to membranes. The results are compared with those obtained in other studies on the subcellular localization of calcium and in biochemical studies on membrane versus matrix loading in calcium-accumulating isolated mitochondria.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0738
    Keywords: Benzydamine ; 1-Benzyl-3-(3-dimethylaminopropoxy)-1H-indazole ; Benzydamine poisoning ; Detection of benzydamine ; Benzydamin ; 1-Benzyl-3-(3-dimethylaminopropoxy)-1H-indazol ; Benzydaminvergiftung ; Benzydaminnachweis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wird über einen Vergiftungsfall durch „Tantum“ (Benzydaminhydrochlorid) bei einem 2 1/2 Jahre alten Mädchen berichtet, wobei das Vergiftungsbild von choreatiformer Bewegungsunruhe, Somnolenz, ängstlichem Gesichtsausdruck und tonischen Streckkrämpfen beherrscht wurde. Der Nachweis von „Tantum“ und eines Abbauproduktes im Urin des Kindes gelang papierchromatographisch und mittels UV-Spektrophotometrie. Eine Arbeitsvorschrift wird angegeben.
    Notes: Summary A case of acute poisoning of a 2 1/2 year old female child who ingested nearly 1 Gm. of benzydamine hydrochloride (Tantum) is described. The predominating symptoms of the poisoning were restlessness with choreiform movements, frightened facial expression and tonic extensor spasms. It was possible to detect both benzydamine and a metabolite in the urine of the child by means of paper chromatography and ultraviolet spectrophotometry. Procedural directions are given.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0827
    Keywords: Cellular calcium ; Electron microscopy ; Osteoblasts ; Chondrocytes ; Mineralization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The calcium distribution in cartilage and bone cells during beginning ossification of fetal mouse long bones was studied after fixation with 2% K-pyroantimonate in 1% osmium. In the developing periosteum, the future osteoblasts showed a sparse cation-antimonate precipitate over the cytoplasm. In young osteoblasts the precipitate was accumulated on the mitochondrial membranes and the plasmalemma. Both organelles were sharply outlined by precipitate in the mature osteoblasts at the onset of mineralization. X-Ray microprobe analysis of these organelles demonstrated the presence of both Sb and Ca. In the extracellular compartment, a collagen-associated precipitate with 50 to 60 nm periodicity appeared during osteoblastic differentiation. During the initial phase of matrix mineralization, a random gross precipitate appeared in the matrix and seemed to be accumulated by osmiophilic matrix vesicles while the collagen fibrils lost their precipitate. Subsequently, during the confluent phase of matrix mineralization, the precipitate rapidly disappeared from the cells, leaving them devoid of precipitate once they were surrounded by mineralized matrix. Similar changes were found in the chondrocytes of the growth plate, but cartilage collagen, unlike osteoid collagen, did not bind precipitate. The results indicate that both osteoblasts and calcifying cartilage cells bind calcium prior to matrix mineralization. Bone collagen has strong pyroantimonate binding capacity, but it is not directly involved with initial stages of matrix mineralization, which starts in close association with matrix vesicles.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Electrochimica Acta 17 (1972), S. 1883-1893 
    ISSN: 0013-4686
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1420-9071
    Keywords: Vicia faba ; endopolyploidy ; nucleolus organizer region ; silver staining ; restitution nucleus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The number of chromatids with transcriptionally active NORs in 4-, 8-, and 16-ploid restitution nuclei, as well as in endopolyploid nuclei with ploidy degrees of 4 and 8, were investigated by Ag-staining. In the genomes studied, the frequency of Ag-dots was equal to the number of chromatid NORs.
    Type of Medium: Electronic Resource
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