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  • 1
    Publikationsdatum: 2018-09-05
    Beschreibung: The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. Methods: We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients with 68 Ga-labeled FAPI. Results: Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracer 18 F-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with 68 Ga but also with therapeutic isotopes such as 177 Lu or 90 Y.
    Print ISSN: 0022-3123
    Thema: Medizin
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Publikationsdatum: 2012-05-02
    Beschreibung: It has been known for nearly 100 years that pressure unfolds proteins, yet the physical basis of this effect is not understood. Unfolding by pressure implies that the molar volume of the unfolded state of a protein is smaller than that of the folded state. This decrease in volume has been proposed to arise from differences between the density of bulk water and water associated with the protein, from pressure-dependent changes in the structure of bulk water, from the loss of internal cavities in the folded states of proteins, or from some combination of these three factors. Here, using 10 cavity-containing variants of staphylococcal nuclease, we demonstrate that pressure unfolds proteins primarily as a result of cavities that are present in the folded state and absent in the unfolded one. High-pressure NMR spectroscopy and simulations constrained by the NMR data were used to describe structural and energetic details of the folding landscape of staphylococcal nuclease that are usually inaccessible with existing experimental approaches using harsher denaturants. Besides solving a 100-year-old conundrum concerning the detailed structural origins of pressure unfolding of proteins, these studies illustrate the promise of pressure perturbation as a unique tool for examining the roles of packing, conformational fluctuations, and water penetration as determinants of solution properties of proteins, and for detecting folding intermediates and other structural details of protein-folding landscapes that are invisible to standard experimental approaches.
    Print ISSN: 0027-8424
    Digitale ISSN: 1091-6490
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Publikationsdatum: 2015-03-11
    Beschreibung: Article The epigenetic factor Bmi1 regulates self-renewal of many adult stem cells, but its role in heart function is unknown. Here the authors show that Bmi1 prevents cardiac senescence by inhibiting the tumor suppressor protein p16 INK4a in adult mice, protecting them from dilated cardiomyopathy and heart failure. Nature Communications doi: 10.1038/ncomms7473 Authors: I. Gonzalez-Valdes, I. Hidalgo, A. Bujarrabal, E. Lara-Pezzi, L. Padron-Barthe, P. Garcia-Pavia, P. Gomez, J.M. Redondo, J.M. Ruiz-Cabello, L.J. Jimenez-Borreguero, J.A. Enriquez, J.L. de la Pompa, A. Hidalgo, S. Gonzalez
    Digitale ISSN: 2041-1723
    Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Publikationsdatum: 2015-05-16
    Beschreibung: Corrigendum Nature Communications doi: 10.1038/ncomms8242 Authors: I. Gonzalez-Valdes, I. Hidalgo, A. Bujarrabal, E. Lara-Pezzi, L. Padron-Barthe, P. Garcia-Pavia, Pablo Gómez-del Arco, J.M. Redondo, J.M. Ruiz-Cabello, L.J. Jimenez-Borreguero, J.A. Enriquez, J.L. de la Pompa, A. Hidalgo, S. Gonzalez
    Digitale ISSN: 2041-1723
    Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Publikationsdatum: 2017-03-08
    Beschreibung: Retraction: Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence Nature Communications, Published online: 7 March 2017; doi:10.1038/ncomms14006
    Digitale ISSN: 2041-1723
    Thema: Biologie , Chemie und Pharmazie , Allgemeine Naturwissenschaft , Physik
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    Digitale Medien
    Digitale Medien
    Amsterdam : Elsevier
    Plant Science 56 (1988), S. 99-106 
    ISSN: 0168-9452
    Schlagwort(e): C"2H"2 reduction ; intracellular pH ; nitrate ; proteolysis ; root nodule ; senescence
    Quelle: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Thema: Biologie
    Materialart: Digitale Medien
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Digitale Medien
    Digitale Medien
    Amsterdam : Elsevier
    Phytochemistry 34 (1993), S. 645-648 
    ISSN: 0031-9422
    Schlagwort(e): (+) abscisic acid metabolism ; Compositae ; Helianthus annuus ; chiral HPLC. ; dihydrophaseic acid glucoside ; embryo dormancy ; sunflower
    Quelle: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Thema: Biologie , Chemie und Pharmazie
    Materialart: Digitale Medien
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Digitale Medien
    Digitale Medien
    Amsterdam : Elsevier
    Scientia Horticulturae 54 (1993), S. 165-174 
    ISSN: 0304-4238
    Schlagwort(e): Buffering capacity ; Rosa hybrida ; cell sap pH ; intracellular pH ; senescence
    Quelle: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Thema: Land- und Forstwirtschaft, Gartenbau, Fischereiwirtschaft, Hauswirtschaft
    Materialart: Digitale Medien
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    Digitale Medien
    Digitale Medien
    Springer
    Planta 152 (1981), S. 336-340 
    ISSN: 1432-2048
    Schlagwort(e): Abscisic acid ; Cotyledons ; Embryonic axis ; Embryo culture ; Pyrus
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie
    Notizen: Abstract Pyrus malus L. var. Golden delicious embryos were incubated with (±)-[2-14C]abscisic acid (ABA) (10-5 M, 355 kBq μmol-1). After incubations of various durations, the radioactivity was measured in whole embryos, cotyledons, and embryonic axes. With either 48-h or 16-d incubation periods, the uptake of [14C]ABA depended upon the mode of culture used. The lowest values corresponded to the absorption by the embryonic axis, the highest to the absorption by the distal parts of the two cotyledons. The cotyledons accumulated the main part of the radioactivity under all conditions. Dormant and almost completely after-ripened embryos cultivated for 4 d showed no significant differences in the radioactivity uptake for identical modes of culture. There was a linear relationship between exogenous ABA concentrations (0.5 to 3.10-5 M) and ABA uptake for embryos cultivated for 4 d with the distal parts of the cotyledons immersed in the medium.
    Materialart: Digitale Medien
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    Digitale Medien
    Digitale Medien
    Springer
    World journal of surgery 7 (1983), S. 363-371 
    ISSN: 1432-2323
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Beschreibung / Inhaltsverzeichnis: Résumé L'étude consécutive de 217 malades atteints de goitre multinodulaire et traités chirurgicalement a permis de constater que 43% d'entre eux présentaient une secrétion hormonale thyroÏdiennes autonome significative ainsi que l'a montré l'absence de réponse après TRH (TSH〈1,0 4 ΜU/ml après injection intra-veineuse (200 mg) ou ingestion (40 mg) s'accompagnant de valeurs normales de l'index FT-4 et de l'index FT-3 (hyperthyroÏdisme préclinique) dans 74% des cas et d'hyperthyroÏdisme dans 26% des cas. Le taux de la secrétion hormonale thyroÏdienne autonome augmentait parallèlement avec le poids du goÎtre et l'âge des malades. La récidive du goÎtre peut Être non seulement TSH dépendante mais elle peut aussi se développer de faÇon autonome à partir du tissu normal laissé en place. Ceci implique la résection sélective du goitre nodulaire au lieu de la résection subtotale uniforme laissant en place des résidus au niveau du hile. Les résultats de la tactique opératoire et de la technique qui furent adoptées en fonction de ces critères sont présentés 1)—la morbidité opératoire fut basse; 2)—chez les malades ne répondant pas au TRH la secrétion hormonale thyroÏdienne autonome fut basse après résection; 3)—aucune hypothyroÏdie ne fut constatée mais une élévation légère de la sécrétion de TSH fut observée chez 40% des opérés; 4)—la surveillance de 76 opérés sélectionnés pendant une période de 3,5 ans révéla la survenue d'une dépendance TSH et d'une récidive autonome se développant au niveau du lobe laissé en place. La résection sélective du goitre est conseillée sur la base de nouvelles conceptions physiopathologiques s'appliquant au goitre multinodulaire bénin et de l'amélioration de la technique de la chirurgie thyroÏdienne.
    Kurzfassung: Abstracto En un estudio prospectivo de 217 pacientes consecutivos con bocio multinodular seleccionados para tratamiento quirÚrgico, 43% presentaron significativa secretion autónoma de hormona tiroidea a juzgar por falta de respuesta a TRH (TSH〈1.0 ΜU/ml después de TRH intravenosa−200 Μg, u oral −40 mg-) con valores normales de índice FT4 e índice FT3 (hipertiroidismo preclínico) en el 47%, y con hipertiroidismo en el 26% de estos casos. La magnitud de secreción autónoma de hormona tiroidea se encontró aumentada en relación al peso promedio del bocio y a la edad de los pacientes. El crecimiento nodular del bocio es considerado como manifestación adicional de escape de la dependencia de TSH, especialmente respecto a la replicación celular del epitelio folicular. La recurrencia del bocio puede no ser, por consiguiente, TSH-dependiente, sino que también puede evolucionar a partir de tejido bocioso residual de crecimiento autónomo. Esto implica una resección selectiva del bocio nodular en vez de la resección subtotal uniforme que deja remanentes en el hilio. Se presentan los resultados prospectivos de esta táctica y técnica operatoria: 1) la morbilidad operatoria fue baja; 2) en pacientes que no respondían a TRH la secreción autónoma de hormona tiroidea postablación fue usualmente baja. La función tiroidea inducida por TRH y TSH apareció recuperada en 2 a 4 meses; 3) no ocurrió hipotiroidismo, pero se presentó una secreción ligeramente elevada de TSH en 40% de los pacientes; 4) el seguimiento de 76 pacientes seleccionados durante un promedio de 3.5 años reveló la ocurrencia de recurrencias TSH-dependientes y recurrencias autónomas en lóbulos no resecados. La resección selectiva es preconizada sobre la base de nuevos conceptos patofisiológicos en el bocio benigno multinodular y sobre la base del refinamiento de la técnica de cirugía tiroidea.
    Notizen: Abstract In a prospective study of 217 consecutive patients with multinodular goiter selected for surgical treatment, 43% had significant autonomous thyroid hormone secretion as evidenced by TRH unresponsiveness [TSH〈1.0 ΜU/ml after intravenous (200 Μg) or oral (40 mg) TRH], with normal values of the FT4-Index and FT3-Index (preclinical hyperthyroidism) in 74%, and with hyperthyroidism in 26% of these cases. The amount of autonomous thyroid hormone secretion increased with the mean goiter weight and age of patients. Nodular goiter growth is considered a further manifestation of escape from normal TSH dependence, namely, with respect to follicular epithelium cell replication. Goiter recurrence may, therefore, not only be TSH dependent, but it may also evolve from autonomously growing goiter tissue left behind. This implies a selective nodular goiter resection instead of the uniform subtotal resection leaving remnants at the hilus. Prospective results of this operative tactic and technique are presented: (a) operative morbidity was low; (b) in TRH-unresponsive patients, the postablative autonomous thyroid hormone secretion was usually low. The thyrotropic and TSH-mediated thyroid function recovered within 2–4 months; (c) no hypothyroidism occurred, but slightly elevated TSH secretion resulted in 40% of the patients; and (d) follow-up of 76 selected patients during a mean of 3.5 years revealed the occurrence of TSH-dependent and of autonomous recurrences, developing in nonresected lobes. Selective goiter resection is advocated on the basis of newer pathophysiological concepts in benign multinodular goiter and on the basis of refinement of the thyroid surgical technique.
    Materialart: Digitale Medien
    Standort Signatur Einschränkungen Verfügbarkeit
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