15 research outputs found

    Personalized medicine: consequences for drug research and therapy

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    In drug research, a serious transformation has taken place. With increasing knowledge gained from molecular medicine, it became possible to refine and develop new therapies based on the molecular mechanisms of diseases. Medicine and drug development have seen a paradigm shift which can be characterized with the catchword ‚Äúpersonalized medicine‚ÄĚ, also called ‚Äústratified medicine‚ÄĚ or ‚Äúprecision medicine‚ÄĚ. Personalized medicine is based on defined tandems of therapeutic agents and diagnostic tests. With this addition to the regular medical examination of the patient, specific patient characteristics are determined. The results of such diagnostic tests are then decisive for the choice of therapy or control of the effectiveness of the chosen treatment. The benefit of personalized medicine for the patient is the higher probability of treatment success as well as improved effectiveness and reduced / avoided side effects. Health insurance systems and the public may have the advantage that the health funds can be used more efficiently on this basis. This new paradigm requires also a new debate on the remuneration in health care. In order to bring personalized therapies to patients as quickly as possible, all players in health care should work together to address the challenges associated with personalized medicine

    Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial

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    Seroprotection rates of vaccine-preventable diseases among newly arrived Eritrean asylum seekers in Switzerland: a cross-sectional study.

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    BACKGROUND According to 2016 WHO/UNICEF country estimates Eritrea has overall high vaccination coverage with immunisation rates for 3 doses of diphtheria/tetanus/pertussis and polio vaccine of 95%, for 2 doses measles vaccine of 85%, and for 3 doses Hepatitis B vaccine of 85%. If confirmed, this could imply that routine basic vaccination of newly arrived Eritreans could be safely omitted. METHODS We used stored serum samples from two cross-sectional studies that screened newly arrived Eritrean refugees for infectious diseases. Consenting refugees aged 16 years and older who registered in one of three neighbouring cantons in northwestern Switzerland were enrolled between January 2016 and December 2017. Antibody titers against the following vaccine-preventable diseases were measured (applied thresholds for seroprotection in brackets): diphtheria (> 0.1 IU/ml), tetanus (> 0.1 IU/ml), measles (> 150 mIU/ml), rubella (only for women,> 11 IU/ml), varicella (> 50 mIU/ml), hepatitis B (HbsAg Index > 0.9, antiHBc Index > 0.9 and antiHBs > 10 IE/L). Differences between sex and age groups (‚ȧ 25 and >25 years) were measured by Fisher's exact test. RESULTS We analysed samples of 133 study participants (20 women, 15%) with a median age of 25 years (range 16-61). Rates of sero-positivity were as follow for women / men respectively: diphtheria 57.9% / 74.8% (difference non significant), tetanus 94.8% / 41.1% (p<0.001), measles 73.7% / 76.6% (non sig.), rubella in women 78.9%, varicella 89.5% / 95.3% (non sig.), anti-HBc 15.8% / 26.2% (non sig.), and anti-HBs 15.8% / 17.8% (non sig.). CONCLUSIONS Sero-prevalence for vaccine-preventable infections did not meet levels required to confer herd-immunity in any of the human-to-human transmissible diseases that were studied. In general, the strategy proposed by the Federal Office of Public Health to offer basic immunization to all newly arrived refugees, including newly arriving Eritrean refugees, is justified

    Functional and protein chemical characterization of the N-terminal domain of the rat corticotropin-releasing factor receptor 1

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    Rat corticotropin-releasing factor receptor 1 (rCRFR1) was produced either in transfected HEK 293 cells as a complex glycosylated protein or in the presence of the mannosidase I inhibitor kifunensine as a high mannose glycosylated protein. The altered glycosylation did not influence the biological function of rCRFR1 as demonstrated by competitive binding of rat urocortin (rUcn) or human/rat corticotropin-releasing factor (h/rCRF) and agonist-induced cAMP accumulation. The low production rate of the N-terminal domain of rCRFR1 (rCRFR1-NT) by transfected HEK 293 cells, was increased by a factor of 100 in the presence of kifunensine. The product, rCRFR1-NT-Kif, bound rUcn specifically (KD = 27 nM) and astressin (KI = 60 nM). This affinity was 10-fold lower than the affinity of full length rCRFR1. However, it was sufficiently high for rCRFR1-NT-Kif to serve as a model for the N-terminal domain of rCRFR1. With protein fragmentation, Edman degradation, and mass spectrometric analysis, evidence was found for the signal peptide cleavage site C-terminally to Thr23 and three disulfide bridges between precursor residues 30 and 54, 44 and 87, and 68 and 102. Of all putative N-glycosylation sites in positions 32, 38, 45, 78, 90, and 98, all Asn residues except for Asn32 were glycosylated to a significant extent. No O-glycosylation was observed

    Arginase Structure and Inhibition: Catalytic Site Plasticity Reveals New Modulation Possibilities

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    Abstract Metalloenzyme arginase is a therapeutically relevant target associated with tumor growth. To fight cancer immunosuppression, arginase activity can be modulated by small chemical inhibitors binding to its catalytic center. To better understand molecular mechanisms of arginase inhibition, a careful computer-aided mechanistic structural investigation of this enzyme was conducted. Using molecular dynamics (MD) simulations in the microsecond range, key regions of the protein active site were identified and their flexibility was evaluated and compared. A cavity opening phenomenon was observed, involving three loops directly interacting with all known ligands, while metal coordinating regions remained motionless. A novel dynamic 3D pharmacophore analysis method termed dynophores has been developed that allows for the construction of a single 3D-model comprising all ligand-enzyme interactions occurring throughout a complete MD trajectory. This new technique for the in silico study of intermolecular interactions allows for loop flexibility analysis coupled with movements and conformational changes of bound ligands. Presented MD studies highlight the plasticity of the size of the arginase active site, leading to the hypothesis that larger ligands can enter the cavity of arginase. Experimental testing of a targeted fragment library substituted by different aliphatic groups validates this hypothesis, paving the way for the design of arginase inhibitors with novel binding patterns
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