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  • 1
    Abstract: Human cytomegalovirus (HCMV) harmfully impacts survival after peripheral blood hematopoietic stem cell transplantation (PB-HSCT). Delayed immune reconstitution after cord blood (CB)-HSCT leads to even higher HCMV-related morbidity and mortality. Towards a feasible dendritic cell therapy to accelerate de novo immunity against HCMV, we validated a tricistronic integrase-defective lentiviral vector (coexpressing GM-CSF, IFN-alpha, and HCMV pp65 antigen) capable to directly induce self-differentiation of PB and CB monocytes into dendritic cells processing pp65 ("SmyleDCpp65"). In vitro, SmyleDCpp65 resisted HCMV infection, activated CD4(+) and CD8(+) T cells and expanded functional pp65-specific memory cytotoxic T lymphocytes (CTLs). CD34(+) cells obtained from PB and CB were transplanted into irradiated NOD.Rag1(-/-).IL2gammac(-/-) mice. Donor-derived SmyleDCpp65 administration after PB-HSCT stimulated peripheral immune effects: lymph node remodeling, expansion of polyclonal effector memory CD8(+) T cells in blood, spleen and bone marrow, and pp65-reactive CTL and IgG responses. SmyleDCpp65 administration after CB-HSCT significantly stimulated thymopoiesis. Expanded frequencies of CD4(+)/CD8(+) T cell precursors containing increased levels of T-cell receptor excision circles in thymus correlated with peripheral expansion of effector memory CTL responses against pp65. The comparative in vivo modeling for PB and CB-HSCT provided dynamic and spatial information regarding human T and B cell reconstitution. In vivo potency supports future clinical development of SmyleDCpp65.
    Type of Publication: Journal article published
    PubMed ID: 26052526
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie; 20180603-20180606; Münster; DOCP022 /20180618/
    Publication Date: 2018-06-19
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS); 20170514-20170517; Magdeburg; DOCP 115 /20170609/
    Publication Date: 2017-06-09
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS); 20170514-20170517; Magdeburg; DOCDI.27.01 /20170609/
    Publication Date: 2017-06-09
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 5
    ISSN: 1433-0393
    Keywords: Key words Nuchal translucency • Human • Mouse • Fetus • Embryo • Trisomy 16 • Trisomy 21 • Trisomy 18 • Trisomy 13 • Gene expression • Collagen type I • Collagen type III • Collagen type IV • Collagen type V • Collagen type VI • Laminin • Fibronectin • Skin • Monoclonal antibodies • Polyclonal antibodies • Immunohistochemistry • In situ hybridization • mRNA • Northern blot • Electron microscopy • Immunogold electron microscopy • Gene dosage effect ; Schlüsselwörter Nuchal translucency • Trisomie • Genexpression • Kollagen • Immunhistochemie • Ductus venosus • Gendosis Effekt
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei etwa 80 % der Feten mit Trisomie 21, 18 oder 13 und dem Turner-Syndrom kann eine Flüssigkeitsansammlung in der Nackenregion zwischen der 10. und 14. SSW beobachtet werden. Diese macht sich als erhöhter Meßwert bei der „nuchal-translucency“ Ultraschalluntersuchung bemerkbar. Die Pathophysiologie dieses allgemein zu beobachtenden Phänotypes unterschiedlicher chromosomaler Störungen ist unklar, aber es gibt einige Hinweise, daß einer der Mechanismen kardiale Herzinsuffizienz sein könnte. Man führt dies auf Anomalien des Herzens und der großen Gefäße zurück, sowie auf Veränderungen der extrazellulären Matrix von Geweben und in der Haut. Letztere könnte Folge eines Gendosiseffekts der 3 Genkopien bei Trisomien, anstatt der normalerweise vorliegenden 2 Genkopien sein, die zu einer Veränderung der extrazellulären Matrix der Haut oder einer abnormalen Entwicklung des Herzens und der großen Arterien führen.
    Notes: Summary In about 80 % of fetuses with trisomies 21, 18 or 13 and Turner syndrome there is an increased collection of fluid in the neck region that can be visualized sonographically at 10–14 weeks gestation as increased nuchal translucency thickness. The pathophysiology of this common phenotypic expression of different chromosomal abnormalities is uncertain, but there is some evidence that the underlying mechanism may be cardiac failure, possibly due to abnormalities of the heart and great arteries, and altered composition of the extracellular matrix of tissues, which can be also noticed in the skin. The latter may be due to a gene dosage effect of the three rather than the normal two copies of genes found in trisomies, causing an alteration of the extracellular matrix in the skin or abnormal development of the heart and great arteries.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0568
    Keywords: Key words Nuchal translucency ; Trisomy 16 ; Trisomy 21 ; Trisomy 18 ; Trisomy 13
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  An increase in the nuchal translucency that can be detected at 10–14 weeks of gestation by ultrasound forms the basis for a screening test for chromosomal abnormality. Several mechanisms leading to this increase in skin thickness have been proposed, including changes of the extracellular matrix, cardiac defects and abnormalities of the large vessels. This study examines the composition of the extracellular matrix of the skin in gestational age-matched fetuses with trisomy 21, 18 and 13 from 12–18 weeks. Immunohistochemistry was applied with monoclonal and polyclonal antibodies against collagen type I, III, IV, V and VI and against laminin and fibronectin. Collagen type VI gene expression was further studied by in situ hybridization to detect differences in expression patterns of COL6A1, COL6A3 and COL1A1 between normal fetuses and those with trisomy 21. The ultrastructure of tissue samples was studied by transmission electron microscopy (TEM) and additionally by immunogold TEM. Further, we examined the morphology of the skin in an animal model for Down’s syndrome, the murine trisomy 16, by light and TEM. The dermis of trisomy 21 fetuses was richer in collagen type VI than that of normal fetuses and other trisomies, and COL6A1, located on chromosome 21, was expressed in a wider area than COL6A3, which is located on chromosome 2. Collagen type I was less abundant in the skin of trisomy 18 fetuses, while the skin of all three trisomies contained a dense network of collagen type III and V in comparison with normal fetuses. Collagen type IV, of which two genes are located on chromosome 13, was expressed in the basement membranes of the skin in all fetuses and additionally in the dermal fibroblasts only of trisomy 13 fetuses. Likewise, laminin was present in all basement membranes of normal and trisomic fetuses as well as in dermal fibroblasts of fetuses with trisomy 18. LAMA1 and LAMA3 genes are located on chromosome 18. Dermal cysts were found in the skin of trisomy 18 and 13, but not in trisomy 21 and normal fetuses. Ultrastructural findings showed that an extracellular precipitate containing glycosaminoglycans was regularly present in the skin of trisomy 21 fetuses and murine trisomy 16 embryos. In conclusion, this study suggests that the skin edema in fetal trisomies is characterized by specific alterations of the extracellular matrix that may be attributed to gene dosage effects as a result of a genetic imbalance due to the condition of fetal trisomy.
    Type of Medium: Electronic Resource
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