A versatile system to introduce clusters of genomic double-strand breaks in large cell populations.

In vitro assays for clustered DNA lesions will facilitate the analysis of the mechanisms underlying complex genome rearrangements such as chromothripsis, including the recruitment of repair factors to sites of DNA double-strand breaks (DSBs). We present a novel method generating localized DNA DSBs using UV irradiation with photomasks. The size of the damage foci and the spacing between lesions are fully adjustable, making the assay suitable for different cell types and targeted areas. We validated this setup with genomically stable epithelial cells, normal fibroblasts, pluripotent stem cells, and patient-derived primary cultures. Our method does not require a specialized device such as a laser, making it accessible to a broad range of users. Sensitization by 5-bromo-2-deoxyuridine incorporation is not required, which enables analyzing the DNA damage response in post-mitotic cells. Irradiated cells can be cultivated further, followed by time-lapse imaging or used for downstream biochemical analyses, thanks to the high throughput of the system. Importantly, we showed genome rearrangements in the irradiated cells, providing a proof of principle for the induction of structural variants by localized DNA lesions.

[Experiences with telepathology in northern Afghanistan : A 10-year success story]. / Erfahrungen mit Telepathologie in Nordafghanistan : Eine 10-jährige Erfolgsgeschichte.

Afghanistan is in a military conflict lasting more than 20 years and according to recent political development, in a downhill spiral towards a failed society. This scenario faces the question of the usefulness of international medical aid, especially morphological diagnostics in crisis situations. On the basis of ten years of experience from a telemedicine project, need, feasibility and results in Afghanistan will be discussed. General and country-specific problems and the sustainability of an international partnership are discussed. In summary our experience is: (1) Telemedicine is possible and necessary even in countries with high conflict potential. It is integrated into routine care by local medical care taker, (2) Accompanying video conferences are a significant improvement in telemedical diagnostics, (3) "High level" consultations can bridge the gap between sophisticated western diagnostics and medicine in the partner country in selected cases and (4) Scientific work is possible on the basis of the medical data collected on site and the image material generated.

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors.

Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n = 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.