The ARGUS Vertex Trigger

A fast second level trigger has been developed for the ARGUS experiment which recognizes tracks originating from the interaction region. The processor compares the hits in the ARGUS Micro Vertex Drift Chamber to 245760 masks stored in random access memories. The masks which are fully defined in three dimensions are able to reject tracks originating in the wall of the narrow beampipe of 10.5\,mm radius.Comment: gzipped Postscript, 27 page

Synthesis and characterisation of novel isoform-selective histone deacetylase inhibitors (HDACi) and HDACi-based multi-target ligands

In the quickly evolving field of epigenetic therapy, histone deacetylases (HDACs) have emerged as preferred targets for the treatment of cancer and other conditions such as viral infections, neurodegenerative disorders, and inflammatory diseases. With several HDAC inhibitors (HDACi) already on the market, the focus has recently shifted to developing isoform-specific inhibitors rather than unselecive drugs. Of the eleven HDAC isoforms known to date, HDAC6 is of particular impotance for drug discovery due to its versatile biological functions. The selective inhibition of HDAC6 can moreover be used to exploit synergistic activites with other epigenetic drugs, especially proteasome inhibitors. The design and synthesis of pan-HDACi and selective HDAC6i accomplished in this work covers a range of different scaffolds. Accessible through multicomponent protocols such as the Ugi four-component reaction and the Ugi-azide four component reaction, two libraries of peptoid-capped HDACi have been assessed in terms of their inhibitory activities and antiproliferative potential as single agents or in combination therapies. Another project realised through multi-step synthesis afforded eleven dual HDAC/proteasome inhibitors with the ability to inhibit both targets through one scaffold. In comparison to combination therapies, such multi-target drugs bring the advantage of more predictable pharmacokinetic profiles and simpler dosing schedules. Lacking the risk of drug-drug interactions, they are moreover expected to induce less severe side-effects. A drawback shared by most current HDACi on the market is the intrinsic toxicity and mutagenic potential of the hydroxamate motif which happens to be the most common zinc-binding group (ZBG) for HDACi. In addition to overcoming the associated risks, alternative ZBGs offer new means to introduce isoform-selectivity into the otherwise highly constricted HDACi pharmacophore model. To this end, one of the projects presented in this work focused on developing a new (difluoromethyl)-1,3,4-oxadiazole-based ZBG for selective HDAC6i

Building Digital Bridges: Exploring the Digitized Collaboration of General Practitioners and Mobile Care in Rural Areas

In the process of digitalization of healthcare, professionals, such as mobile care nurses or general practitioners, are facing both new challenges and opportunities. Digital technologies thereby promise to affect the cooperation of healthcare professionals on various levels, e.g., increasing quality of care, improving interprofessional communication, or optimizing economic aspects of care. Our study examines current issues of healthcare professionals concerning a digital change of care. We conducted qualitative interviews with primary care practitioners and providers of mobile care (nurses and care managers) to understand perceived obstacles in the process of digitalization and to formulate possible implications to encounter those obstacles. Our results suggest that insufficient communication and a lack of mutual trust have to be considered relevant issues. We therefore propose to focus future research on the interchangeability of different communication and documentation systems

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs)

Limits for the central production of Θ+ and Ξ−− pentaquarks in 920-GeV pA collisions

We have searched for Θ+(1540) and Ξ−−(1862) pentaquark candidates in proton-inducedreactions on C, Ti, and W targets at midrapidity and s√=41.6  GeV. In 2×108 inelastic eventswe find no evidence for narrow (σ≈5  MeV) signals in the Θ+→pK0S and Ξ−−→Ξ−π− channels; our 95% C.L. upper limits (UL) forthe inclusive production cross section times branching fraction B dσ/dy $y ≈0 are (4-16) μb/N for a Θ+ mass between 1521 and 1555 MeV,and 2.5μb/N for the Ξ−−. The UL of the yield ratio of Θ+/Λ(1520)<(3-12)% is significantly lower than model predictions.Our UL of B Ξ−−/Ξ(1530)0<4% is at variance with the results that have provided the first evidencefor the Ξ−−

A Search for the Electric Dipole Moment of the Tau-Lepton

Using the ARGUS detector at the e+e- storage ring DORIS II, we have searched for the real and imaginary part of the electric dipole formfactor d_tau of the tau lepton in the production of tau pairs at q^2=100 GeV^2. This is the first direct measurement of this CP violating formfactor. We applied the method of optimised observables which takes into account all available information on the observed tau decay products. No evidence for CP violation was found, and we derive the following results: Re(d_tau)=(1.6+-.9)*10^(-16) ecm and Im(d_tau)=(-0.2+-0.8)*10^(-16) ecm, where statistical and systematic errors have been combined.Comment: 8 pages, 5 figures (10 subfigures