Development of a novel 3D human cartilage model system to investigate changes in cartilage associated with osteoarthritis

Osteoarthritis (OA) is the most prevalent form of degenerative joint diseases and affects about 13% of the world’s population with patients over 65 years of age reflecting the largest group of patients (Matthews and Hunter 2011). OA is characterized by a progressive degeneration of joint cartilage and results in impaired function of affected joints, pain and negatively affects quality of life of patients. Several biomarkers for the detection of early OA were already described (Mobasheri 2013), but none of them is reliable and quantifiable.Therefore, a need for novel biomarkers for OA exists to improve diagnosis when overt changes in cartilage are not yet detectable.The aim of my thesis was to identify novel biomarkers for OA which can be used for early diagnosis. I focused on changes in the glycosylation of proteoglycans, especially on chondroitin sulphate (CS) glycosaminoglycan (GAG) chains. Using human chondrocyte progenitor cells, a novel 3D cartilage model was developed and characterized. The resulting cartilage constructs showed similar biochemical, histological and mechanical properties like native articular cartilage. To investigate the effects of inflammatory cytokines, which are also present in OA, on changes in expression of glycosylation-related genes, treated and untreated constructs were analyzed using microarrays.Analysis showed that although genes for GAG chain synthesis were downregulated,the sulphotransferase GalNAc4S-6ST was significantly upregulated. This enzyme catalyzes the formation of GalNAc4,6diS, which has high biological activity (Mikami and Kitagawa 2013). In addition, the expression of serglycin was strongly increased after inflammatory stimulation. These results show that novel epitopes containing GalNAc4,6diS or serglycin could be potential biomarkers for OA. Besides the experiments with cartilage constructs, analysis of the CS chain of decorin isolated from human skin fibroblasts showed that inflammatory stimulation alters the length and composition of CS chains

Rescuing DNA repair activity by rewiring the H-atom transfer pathway in the radical SAM enzyme, spore photoproduct lyase

The radical SAM enzyme, spore photoproduct lyase, requires an H-atom transfer (HAT) pathway to catalyze DNA repair. By rational engineering, we demonstrate that it is possible to rewire its HAT pathway, a first step toward the development of novel catalysts based on the radical SAM enzyme scaffold

HEJ 2: High energy resummation for hadron colliders

We present HEJ 2, a new implementation of the High Energy Jets formalism for high-energy resummation in hadron-collider processes as a flexible Monte Carlo event generator. In combination with a conventional fixed-order event generator, HEJ 2 can be used to obtain greatly improved predictions for a number of phenomenologically important processes by adding all-order logarithmic corrections in . A prime example for such a process is the gluon-fusion production of a Higgs boson in association with widely separated jets, which constitutes the dominant background to Higgs boson production in weak-boson fusion

La santé des mamelles dans les fermes laitières

Dans un projet de recherche sur 100 exploitations laitières le FiBL a développé et mis au point - avec l'aide financière du fonds Coop Naturaplan - un procédé alternatif, éthique et écologique pour l'assainissement des mamelles. La fiche téchnique contient des recommandations d' assainissement par étape des mamelles chez la vache laitière et conforme aux directives bio. Les mesures pour maintenir la santé des mammelles sans antibiotiques à long terme sont également présentées

The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients

Background: In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time “liquid biopsy” approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC. Methods: CTC-positive (five or more CTCs/7.5 mL blood; CellSearch®, Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch®). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan–Meier plots. Results: One hundred seven patients (median age (range) 57 (33–81) years) were included. 100/107 (93 %) patients were followed-up for a median [95 % confidence interval (CI)] of 28.5 [25.1–40.1] months. Of 37/107 (35 %) CTC-HER2-positive patients only 10 (27 %) were PRIM-HER2-positive. 6/46 (13 %) patients were MET-HER2-positive; only 2/10 (20 %) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69 % and 74 %, respectively. Kaplan–Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95 % CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7–13.7] versus 4.34 [3.5–5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7–30.0] versus 8.7 [5.9–15.3] months; p = 0.287). Conclusions: HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform “liquid biopsy” to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed

Development of a ³He magnetometer for a neutron electric dipole moment experiment

We have developed a highly sensitive 3He magnetometer for the accurate measurement of the magnetic field in an experiment searching for an electric dipole moment of the neutron. By measuring the Larmor frequency of nuclear spin polarized 3He atoms a sensitivity on the femto-Tesla scale can be achieved. A 3He/Cs-test facility was established at the Institute of Physics of the Johannes Gutenberg University in Mainz to investigate the readout of 3He free induction decay with a lamp-pumped Cs magnetometer. For this we designed and built an ultra-compact and transportable polarizer unit which polarizes 3He gas up to 55% by metastability exchange optical pumping. The polarized 3He was successfully transfered from the polarizer into a glass cell mounted in a magnetic shield and the 3He free induction decay was detected by a lamp-pumped Cs magnetometer.PACS numbers07.55.Ge Magnetometers for magnetic field measurements; 13.40 Electric and magnetic moments; 14.20 Protons and neutrons

Study of ³He Rabi nutations by optically-pumped cesium magnetometers

We describe a method for recording the Rabi nutation of nuclear spin polarized ³He by optically pumped cesium magnetometers. The measurement is performed by detecting the time-dependent magnetic field produced by the 3He magnetization. The observed signals are compared to theoretical models and the results are used to precisely trace the evolution of the magnetization. This procedure represents a convenient way to control and measure the Rabi flip angle and the degree of spin polarization in experiments using 3He magnetometers. The method requires only very coarse knowledge of the applied magnetic field’s magnitude