Biomedical subjects

Wolfgang Schäfer

Publications and source records attributed to Wolfgang Schäfer.

6 recordsLinked to original sources

PubMed2006

Sphingosine 1-phosphate protects ovaries from chemotherapy-induced damage in vivo.

OBJECTIVE: To investigate whether sphingosine-1-phosphate (S1P), an apoptosis-inhibitor, would be able to protect ovarian follicles from chemotherapy-induced cell death in vivo. DESIGN: Animal study. SETTING: Academic medical center. ANIMAL(S): Twenty female mice. INTERVENTION(S): Twenty mice were randomly assigned into three groups: in group A (n = 8), each mouse received an injection of low concentration of S1P (A1: 0.5 mM), prepared in a vehicle (PET) into the bursa of one ovary and a high concentration (A2: 2.0 mM S1P) to the contralateral ovary. In group B (n = 8), only PET was injected to both ovaries. Afterwards, both groups received 100 mug Dacarbazine (Medac, Hamburg, Germany) IV. The control group C (n = 4) received no chemotherapy. After 2 weeks, the ovaries from group C and from 4 mice from group A and B were evaluated histologically. The remaining mice from group A and B were allowed 3 mating attempts at 4, 8, and 12 weeks after chemotherapy. MAIN OUTCOME MEASURE(S): Primordial/primary and pre-/antral follicular density, pregnancy rates. RESULTS: Chemotherapy caused a significant reduction in the mean number of primordial follicles of mice treated with only PET or with low concentration of S1P (1.86/field of view [C] vs. 1.17 [B] and 0.98 [A1]; P=.006 and P<.0001, respectively) but not in the ovaries treated with high concentration of S1P (2.05/field of view [A2]; P=.918, not significant). Furthermore, three mice (75%) from group A became pregnant at the first mating attempt, in contrast to group B, in which only one mouse (25%) became pregnant and only after the third mating attempt. CONCLUSION(S): Local application of S1P protects ovarian follicles from chemotherapy-induced cell death, thereby preserving fertility.

Animals↗

PubMed2006

Intensity of androgen and epidermal growth factor receptor immunoreactivity in samples of radical prostatectomy as prognostic indicator: correlation with clinical data of long-term observations.

PURPOSE: We analyzed the potential prognostic significance of the immunohistochemical expression of androgen and growth factor receptors determined in prostatectomy specimens of patients with prostate cancer. MATERIALS AND METHODS: A cohort of 211 patients with locally confined prostate cancer treated with radical prostatectomy with or without antiandrogen pretreatment between January 1, 1990 and August 31, 1996 was observed prospectively. Prostatectomy samples were processed immunohistochemically to visualize androgen and growth factor receptors, of which immunoreaction intensity was scored relative to that of positive control tissue. Clinical postoperative data were processed using the Kaplan-Meier method, log rank test, and univariate and multivariate explorative Cox modeling to evaluate the contribution to overall and relapse-free survival. RESULTS: There were statistical dependencies between the androgen receptor and epidermal growth factor receptor staining indexes. Following data stratification according to the epidermal growth factor receptor staining index the prognosis associated with a low androgen receptor staining index was worse than that with a higher androgen receptor staining index. Cox regression analysis for relapse-free survival confirmed that the risk factors low androgen receptor and increased epidermal growth factor receptor staining were associated with significantly increased relative risk. Univariate Kaplan-Meier analysis showed that patients with grade 3 carcinoma had a worse prognosis than those with better differentiated carcinoma, whereas antiandrogen pretreatment had no influence on overall survival or relapse-free survival. CONCLUSIONS: Using a multivariate proportional hazards regression model for data on a cohort of 211 patients with 68 showing relapse/progress or death from disease a low intensity of androgen receptor staining indicated a poor prognosis.

Adult↗

PubMed2005

Crystal structures of active SRC kinase domain complexes.

c-Src was the first proto-oncoprotein to be identified, and has become the focus of many drug discovery programs. Src structures of a major inactive form have shown how the protein kinase is rigidified by several interdomain interactions; active configurations of Src are generated by release from this "assembled" or "bundled" form. Despite the importance of Src as a drug target, there is relatively little structural information available regarding the presumably more flexible active forms. Here we report three crystal structures of a dimeric active c-Src kinase domain, in an apo and two ligand complexed forms, with resolutions ranging from 2.9A to 1.95A. The structures show how the kinase domain, in the absence of the rigidifying interdomain interactions of the inactivation state, adopts a more open and flexible conformation. The ATP site inhibitor CGP77675 binds to the protein kinase with canonical hinge hydrogen bonds and also to the c-Src specific threonine 340. In contrast to purvalanol B binding in CDK2, purvalanol A binds in c-Src with a conformational change in a more open ATP pocket.

Animals↗

PubMed2005

Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants.

Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.

Adenosine Triphosphate↗

PubMed2004

High-resolution transthoracic real-time three-dimensional echocardiography: quantitation of cardiac volumes and function using semi-automatic border detection and comparison with cardiac magnetic resonance imaging.

OBJECTIVES: We sought to validate high-resolution transthoracic real-time (RT) three-dimensional echocardiography (3DE), in combination with a novel semi-automatic contour detection algorithm, for the assessment of left ventricular (LV) volumes and function in patients. BACKGROUND: Quantitative RT-3DE has been limited by impaired image quality and time-consuming manual data analysis. METHODS: Twenty-four subjects with abnormal (n = 14) or normal (n = 10) LVs were investigated. The results for end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) obtained by manual tracing were compared with the results determined by the semi-automatic border detection algorithm. Moreover, the results of the semi-automatic method were compared with volumes and EF obtained by cardiac magnetic resonance imaging (CMRI). RESULTS: Excellent correlation coefficients (r = 0.98 to 0.99) and low variability (EDV -1.3 +/- 8.6 ml; ESV -0.2 +/- 5.4 ml; EF -0.1 +/- 2.7%; p = NS) were observed between the semi-automatically and manually assessed data. The RT-3DE data correlated highly with CMRI (r = 0.98). However, LV volumes were underestimated by RT-3DE compared with CMRI (EDV -13.6 +/- 18.9 ml, p = 0.002; ESV -12.8 +/- 20.5 ml, p = 0.005). The difference for EF was not significant between the two methods (EF 0.9 +/- 4.4%, p = NS). Observer variability was acceptable, and repeatability of the method was excellent. CONCLUSIONS: The RT-3DE, in combination with a semi-automatic contour tracing algorithm, allows accurate determination of cardiac volumes and function compared with both manual tracing and CMRI. High repeatability suggests applicability of the method for the serial follow-up of patients with cardiac disease.

Aged↗

PubMed2003

[Structure and limitations of German hospitals with regard to the future--the example of the Vivantes Group].

The German health care system is marked by increasing tension between rising needs, financiability and reformability. Structural deficits and a high performance potential are typical of the German hospital system. In these terms, Berlin occupies a leading position in the intra-national comparison. The introduction of a new payment system for hospitals that is based on case fees (DRGs) will lead to a radical reorganisation of hospitals in both quantity and structure. The health care provider Vivantes brings a clear answer to this challenge: even today this group offers a graduated and complex network integrating outpatient, inpatient, nursing and rehabilitative care units--whilst steadily reducing the capacities required. The integration of external enterprises is capable of improving the network both qualitatively and economically and offering a win-win situation. Integrative purchase-of-service contracts should be formulated to give a noticeable advantage to providers, sickness funds and insured persons.

Delivery of Health Care↗