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  • 25.85.Jg  (1)
  • 1
    Abstract: Cervical cancer is caused by high-risk human papillomaviruses (HPV), in more than half of the worldwide cases by HPV16. Viral DNA integration into the host genome is a frequent mutation in cervical carcinogenesis. Because integration occurs into different genomic locations, it creates unique viral-cellular DNA junctions in every single case. This singularity complicates the precise identification of HPV integration sites enormously. We report here the development of a novel multiplex strategy for sequence determination of HPV16 DNA integration sites. It includes DNA fragmentation and adapter tagging, PCR enrichment of the HPV16 early region, Illumina next-generation sequencing, data processing, and validation of candidate integration sites by junction-PCR. This strategy was performed with 51 cervical cancer samples (47 primary tumors and 4 cell lines). Altogether 75 HPV16 integration sites (3'-junctions) were identified and assigned to the individual samples. By comparing the DNA junctions with the presence of viral oncogene fusion transcripts, 44 tumors could be classified into four groups: Tumors with one transcriptionally active HPV16 integrate (n = 12), tumors with transcribed and silent DNA junctions (n = 8), tumors carrying episomal HPV16 DNA (n = 10), and tumors with one to six DNA junctions, but without fusion transcripts (n = 14). The 3'-breakpoints of integrated HPV16 DNA show a statistically significant (p〈0.05) preferential distribution within the early region segment upstream of the major splice acceptor underscoring the importance of deregulated viral oncogene expression for carcinogenesis. Half of the mapped HPV16 integration sites target cellular genes pointing to a direct influence of HPV integration on host genes (insertional mutagenesis). In summary, the multiplex strategy for HPV16 integration site determination worked very efficiently. It will open new avenues for comprehensive mapping of HPV integration sites and for the possible use of HPV integration sites as individualized biomarkers after cancer treatment of patients for the early diagnosis of residual and recurrent disease.
    Type of Publication: Journal article published
    PubMed ID: 23824673
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  • 2
    ISSN: 1434-601X
    Keywords: 25.20.Dc ; 25.85.Jg ; 27.90.+b
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The total photofission cross section σγ,F for235U and238U has been measured in the energy range 50≤E γ≤800 MeV at the 855 MeV Mainz Microtron MAMI using energy and time tagged photons (Glasgow Tagger) and a 4π arrangement of position sensitive fragment detectors. Besides the absolute photofission cross section σγF , which almost completely exhausts the total photon absorption cross section for these nuclei, fragment mass distributions in this energy domain were determined via time of flight techniques (TOF). The results for the total photofission cross sections σγ,F normalized to the atomic numberA for both isotopes coincide, and agree in theΔ-resonance region, within the systematic errors, with the socalled“Universal Curve” σγ,T /A of the total photon absorption cross section σγ,T . At higher energies the cross sections exhibit a smooth behaviour. In particular, it is shown for the first time that there isno resonance-like shape near the D13 resonance (at ≈710 MeV) as observed for the free proton. This complete suppression of the D13 resonance in complex nuclei is not yet understood on a microscopic level. The fragment mass distributions show a predominantly mass symmetric fission. However, contributions from mass asymmetric fission at some photon energies may give a hint of an increased mass asymmetric fission after the onset of the pion and two pion channels.
    Type of Medium: Electronic Resource
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