DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin

DNA double-strand breaks (DSBs) can induce chromosomal aberrations and carcinogenesis and their correct repair is crucial for genetic stability. The cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (γH2AX). However, a lack of γH2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine γH2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA. Given the linear particle path, such bending indicates a relocation of damage from the initial induction site to the periphery of HC. Real-time imaging of the repair protein GFP-XRCC1 confirms fast recruitment to heterochromatic lesions inside murine chromocenters. Using single-ion microirradiation to induce localized DSBs directly within chromocenters, we demonstrate that H2AX is early phosphorylated within HC, but the damage site is subsequently expelled from the center to the periphery of chromocenters within ∼20 min. While this process can occur in the absence of ATM kinase, the repair of DSBs bordering HC requires the protein. Finally, we describe a local decondensation of HC at the sites of ion hits, potentially allowing for DSB movement via physical forces

DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin

DNA double-strand breaks (DSBs) can induce chromosomal aberrations and carcinogenesis and their correct repair is crucial for genetic stability. The cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (γH2AX). However, a lack of γH2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine γH2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA. Given the linear particle path, such bending indicates a relocation of damage from the initial induction site to the periphery of HC. Real-time imaging of the repair protein GFP-XRCC1 confirms fast recruitment to heterochromatic lesions inside murine chromocenters. Using single-ion microirradiation to induce localized DSBs directly within chromocenters, we demonstrate that H2AX is early phosphorylated within HC, but the damage site is subsequently expelled from the center to the periphery of chromocenters within ∼20 min. While this process can occur in the absence of ATM kinase, the repair of DSBs bordering HC requires the protein. Finally, we describe a local decondensation of HC at the sites of ion hits, potentially allowing for DSB movement via physical forces

Role of Pelvic Lymph Node Dissection in Prostate Cancer Treatment

Pelvic lymph node dissection (PLND) is the most accurate and reliable staging procedure for detecting lymph node invasion (LNI) in prostate cancer. Recently, [11C]-choline positron emission tomography imaging and magnetic resonance imaging with lymphotropic superpara-magnetic nanoparticles have shown potential for detecting LNI but are still under investigation. The risk of LNI in low-risk groups could be underestimated by use of the current nomograms, which rely on data collected from patients who underwent only limited PLND. Extended PLND (ePLND) shows higher lymph node yield, which leads to the removal of more positive nodes and fewer missed positive nodes. It may be possible to refrain from performing PLND on low-risk patients with a prostate-specific antigen value <10 ng/ml and a biopsy Gleason score ≤6, but the risk of biopsy-related understaging should be kept in mind. Theoretically, meticulous ePLND may also impact prostate cancer survival by clearing low-volume diseases and occult micrometastasis even in pN0. The therapeutic role of PLND in prostate cancer patients is still an open question, especially in individuals with low-risk disease. Patients with intermediate- to high-risk disease are more likely to benefit from ePLND

Skeletal Diversification via Heteroatom Linkage Control: Preparation of Bicyclic and Spirocyclic Scaffolds from NSubstituted Homopropargyl Alcohols

The discovery and application of a new branching pathway synthesis strategy that rapidly produces skeletally diverse scaffolds is described. Two different scaffold types, one a bicyclic iodo-vinylidene tertiary amine/tertiary alcohol and the other, a spirocyclic 3-furanone, are each obtained using a two-step sequence featuring a common first step. Both scaffold types lead to intermediates that can be orthogonally diversified using the same final components. One of the scaffold types was obtained in sufficiently high yield that it was immediately used to produce a 97-compound library

Project Da CaPo++, Volume III: Performance Evaluations

Performance evaluations of advanced communication subsystems and their applications are necessary methods to prove that a certain level of communication functionality demanded and a required minimal processing power of end-systems (workstations) and of intermediate systems (networks and routers) have been achieved. The communication middleware package Da CaPo++ provides a modern communication platform that supports flexible communication services, in particular for end-systems. Based on an implementation of Da CaPo++ on workstations (Sun SPARCStations and Sun UltraSPARCs) a performance evaluation has been carried out. Specifically, the performance for relevant communication tasks is identified and overhead required for providing various degrees of communication service flexibility is illustrated

Project Da CaPo++, Volume II : Implementation Documentation

The research project KTI Da CaPo++ is based on the project Da CaPo (Dynamic Configuration of Protocols) at the ETH. The extended system of Da CaPo++ provides a basis for an application framework for banking environments and tele-seminars. It includes the support of prototypical multimedia applications to be used on top of high-speed networks including dynamically configurable security and multicast aspects.The main goal for this document is the description of the implemented design as stated elsewhere. It covers the application framework parts carried out at ETH and Da CaPo++ core system internal details concerning the security and relevant C-modules. These goals have been achieved and implemented under Solaris 2.5.1 on Sun workstations including multimedia equipment, such as cameras, microphones, and speakers.Finally, the implemented design of Da CaPo++ has remained independent of any specific transport infrastructure, as long as the considered network offers minimal features, e.g., bandwidth, delay, or bit error rates that are requested by an application. A heterogeneous infrastructure, including Ethernet and ATM (Asynchronous Transfer Mode), is supported, which has been demonstrated in the final project demonstration July 1, 1997