TY  - JOUR
A1  - Stepniak, Beata
A1  - Kästner, Anne
A1  - Poggi, Giulia
A1  - Mitjans, Marina
A1  - Begemann, Martin
A1  - Hartmann, Annette
A1  - Van der Auwera, Sandra
A1  - Sananbenesi, Farahnaz
A1  - Krüger-Burg, Dilja
A1  - Matuszko, Gabriela
A1  - Brosi, Cornelia
A1  - Homuth, Georg
A1  - Völzke, Henry
A1  - Benseler, Fritz
A1  - Bagni, Claudia
A1  - Fischer, Utz
A1  - Dityatev, Alexander
A1  - Grabe, Hans-Jörgen
A1  - Rujescu, Dan
A1  - Fischer, Andre
A1  - Ehrenreich, Hannelore
T1  - Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes
JF  - EMBO Molecular Medicine
N2  - Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high-versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
KW  - permutation
KW  - miR-181
KW  - PGAS
KW  - FXR2
KW  - FXR1
KW  - FMR2
KW  - FMR1
KW  - identification
KW  - protein
KW  - fraxe mental retardation
KW  - CGG repeat
KW  - CPG Island
KW  - schizophrenia
KW  - expression
KW  - males
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136893
VL  - 7
IS  - 12
ER  - 
TY  - JOUR
A1  - Tsoneva, Desislava
A1  - Stritzker, Jochen
A1  - Bedenk, Kristina
A1  - Zhang, Qian
A1  - Cappello, Joseph
A1  - Fischer, Utz
A1  - Szalay, Aladar A.
T1  - Drug-encoded Biomarkers for Monitoring Biological Therapies
JF  - PLoS One
N2  - Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA) and Staphylococcus sp. RLH1 (GusPlus), and the luciferase from Gaussia princeps (GLuc). The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml) and GLuc (≥375 pg/ml). Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.
KW  - mouse models
KW  - vaccinia virus
KW  - luciferase
KW  - biomarkers
KW  - cytolysis
KW  - viral replication
KW  - cell cultures
KW  - blood
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125265
VL  - 10
IS  - 9
ER  -