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Patients with inflammatory bowel diseases, i. e., ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC.In this study, we aimed to analyze the genetic events that define CD-CRCs, in particular the dynamics of their development from histologically undetectable precursor lesions to invasive disease.We analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions by next generation sequencing (563 gene panel) and array-based comparative genomic hybridization. The results were compared with our own data and the Cancer Genome Atlas data on sporadic CRC.The gain of 5p was significantly more prevalent in CD-CRCs than in sporadic CRCs, despite an overall similar chromosomal aberration pattern. CD-CRCs had a distinct mutation signature with TP53 being the most frequently mutated gene in CD-CRCs. TP53 mutations and copy number alterations were early events in CD progression and could sometimes already be detected in non-dysplastic colonic mucosa, indicating occult tumor evolution.Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: gains of 5p and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predict disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.

A circumscribed association between copy number variations and the diagnosis of schizophrenia or autism but not bipolar disorder supports the notion of schizophrenia and autism principally representing a disturbed brain development. Data of multiply affected families show certain brain structural (e. g. hippocampal) changes to also be present in their first-grade relatives without leading to psychopathological abnormalities. It thus can be concluded that there exist regional fronto-temporal changes in schizophrenia due to genetically early determined primary vulnerability. The transition of this vulnerability into a prodrome to the point of the fully developed disease is triggered by relevant environmental factors. Hippocampal brain structural changes do not base on neuronal loss, for which reason the underlying mechanism might be a reduction of neuropil and thus a disturbance of synaptic processes or even regenerative mechanisms. Thus, disturbed regenerative mechanisms might be linked to the course of schizophrenic psychosis: the more pronounced the negative symptoms, the more evident the impaired synaptic or neuronal plasticity. Based on initial data we speculate the disturbed synaptic/plastic processes to result from an impaired epigenetic regulation. This could explain how relevant environmental factors (pregnancy and birth complications, early childhood abuse or cannabis abuse) via risk genes might lead to a destabilized neuronal network which in the end could trigger schizophrenia symptoms on the behavioral level.

Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N -acetyl- d -glucosamine ( O -GlcNAc), we evaluated whether increased O -GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O -GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O -GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O -GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4 + T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O -GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O -GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O -GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS.

Various microsatellite and CGH studies in prostate cancer identify deletions on the short arm of chromosome 8 especially at band 8p21-22 searching for unknown putative tumor suppressor genes. By means of microsatellite markers several candidate genes were detected which may play different roles in early prostate cancer progression. We established a quantitative gene dosage PCR based on the real time PCR method serving the purpose of genomic fine mapping. Therefore we used 10 Assays-on Demand (ABI) for the detection of deletions located between and nearby the microsatellite markers D8S258 and NEFL spanning a genomic region of approximate 7 mbp. Comparative immunohistochemical analysis from tissue micro arrays (TMA) of 1122 independent cases followed. We were able to detect three clearly separated deletion intervals on 8p21-22. One on LZTS1, second on NEFL and third a deletion hot spot on LOXL2, which was affected in 72% of all investigated cases. Our comparative immunohistochemical TMA based studies demonstrate that LOXL2 is nearly lost in most prostate cancer tissues. LOXL2 catalyze the crosslinking of collagen and elastin in the extracellular matrix and it has been assumed that it is involved in tumor suppression and cell adhesion. LOXL2 is frequently expressed in proliferating tissues and shows a high expression in benign prostate tissue too. In prostate cancer the expression is positive correlated with the MIB1-score.

Objective Human osteoarthritis (OA) is characterized by a pathologic shift in articular cartilage homeostasis toward the progressive loss of extracellular matrix (ECM). The purpose of this study was to investigate the ability of rAAV-mediated SOX9 overexpression to restore major ECM components in human OA articular cartilage. Methods We monitored the synthesis and content of proteoglycans and type II collagen in 3-dimensional cultures of human normal and OA articular chondrocytes and in explant cultures of human normal and OA articular cartilage following direct application of a recombinant adeno-associated virus (rAAV) SOX9 vector in vitro and in situ. We also analyzed the effects of this treatment on cell proliferation in these systems. Results Following SOX9 gene transfer, expression levels of proteoglycans and type II collagen increased over time in normal and OA articular chondrocytes in vitro. In situ, overexpression of SOX9 in normal and OA articular cartilage stimulated proteoglycan and type II collagen synthesis in a dose-dependent manner. These effects were not associated with changes in chondrocyte proliferation. Notably, expression of the 2 principal matrix components could be restored in OA articular cartilage to levels similar to those in normal cartilage. Conclusion These data support the concept of using direct, rAAV-mediated transfer of chondrogenic genes to articular cartilage for the treatment of OA in humans.