Biomedical subjects

J Zimmermann

Publications and source records attributed to J Zimmermann.

At least 19 recordsLinked to original sources

PubMed2006

Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation.

Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BM-), 28 patients with breast carcinoma and BM (BC/BM+) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFbeta1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b (+95%, P=0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P=0.006), MMP-7 (P=0.004) and TIMP-1 (P=0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients.

Biomarkers, Tumor↗

PubMed2006

Adapters, shims, and glue--service interoperability for in silico experiments.

MOTIVATION: Computationally, in silico experiments in biology are workflows describing the collaboration of people, data and methods. The Grid and Web services are proposed to be the next generation infrastructure supporting the deployment of bioinformatics workflows. But the growing number of autonomous and heterogeneous services pose challenges to the used middleware w.r.t. composition, i.e. discovery and interoperability of services required within in silico experiments. In the IRIS project, we handle the problem of service interoperability by a semi-automatic procedure for identifying and placing customizable adapters into workflows built by service composition. RESULTS: We show the effectiveness and robustness of the software-aided composition procedure by a case study in the field of life science. In this study we combine different database services with different analysis services with the objective of discovering required adapters. Our experiments show that we can identify relevant adapters with high precision and recall.

Computational Biology↗

PubMed2006

[Suicide attempts in alcohol dependents: clinical characteristics und differentiation of the applied methods].

INTRODUCTION: Suicidal behavior is common in alcohol-dependent subjects. In terms of methods used, violent and non-violent suicide attempts can be distinguished. To confirm the validity of this distinction from a clinical point of view a sample of inpatient alcohol-dependent subjects is explored. METHODS: Subjects with a diagnosis of alcohol dependence according to DSM-IV and ICD-10 who took part in an inpatient withdrawal treatment program were included. Characteristics of alcohol dependence and suicidal behavior as well as lifetime diagnosis of other psychiatric disorders were assessed using the SSAGA. Clinical syndromes, personality and temperament were obtained by MMPI-2, TCI and NEO-FFI. RESULTS: Of the 182 included patients, alcoholics with a history of suicide attempts reported more depressive pathology and a personality profile characterized by emotional instability, psychopathy and decreased self-control. DISCUSSION: Distinguishing alcohol dependent suicide attempters according to methods used, no significant differences between violent and non-violent methods could be found. Therefore the clinical validity of this distinction could not be confirmed.

Adult↗

PubMed2006

Recombinant variants of antibody 138H11 against human gamma-glutamyltransferase for targeting renal cell carcinoma.

The monoconal antibody 138H11 recognizes human renal gamma-glutamyltransferase (GGT), an antigen shown to allow targeting primary and metastatic renal cell carcinoma (RCC). We determined the primary structure of the antigen binding region of mAb 138H11 and generated several different recombinant antibody variants. First, monomeric single-chain Fv antibody fragments, diabodies and triabodies were obtained by constructing linker variants consisting of 18, 10, 8, 5, 3, 2, 1 and zero amino acid residues, resulting in significant differences in yield and molecular architecture. Second, two variants of disulphide bond-stabilised Fv fragments (dsFvs) were generated using two different pairs of complementary framework amino acid positions of VH and VL for disulphide stabilisation. The binding activities of diabodies to human GGT located on its tissue decreased when using shorter linker lengths. The scFv dimer containing a 3 amino acid residue linker peptide and one of the dsFv variants were not functional. Further, the work paves the way for generating new effector constructs and a systematic optimisation of the pharmacokinetics of this tumor targeting antibody by offering variants with a broad range of valencies and molecular masses.

Amino Acid Sequence↗

PubMed2005

Tubular occlusion prevents water-treeing and through-and-through fluid movement in a single-bottle, one-step self-etch adhesive model.

Water entrapment occurs at resin-dentin interfaces of one-step self-etch adhesives. We hypothesized that by preventing water fluxes from dentin, any water entrapment would be attributed to incomplete removal of adhesive solvents. We tested this hypothesis by bonding to transparent carious dentin containing occluded dentinal tubules. An experimental single-bottle, one-step self-etch adhesive was applied to flat surfaces of caries-affected dentin surrounded by sound dentin, with or without pulpal pressure. Resin-dentin interfaces were examined with TEM after silver-impregnation. Although caries-affected dentin was highly porous, adhesive layers were devoid of silver deposits when tubules were occluded. Conversely, variable extents of water-treeing and water-droplets were identified from adhesive layers in bonded sound dentin. Water-treeing and water-droplet formation, being manifestations of evaporative and convective water fluxes, can be eliminated during bonding to occluded transparent carious dentin. However, the highly porous nature of this clinically relevant substrate after bonding may lead to potentially undesirable consequences.

Acid Etching, Dental↗

PubMed2005

Metal concentrations in soil and seepage water due to infiltration of roof runoff by long term numerical modelling.

The qualitative effects of stormwater infiltration on soil and seepage water are investigated with long term numerical modelling. The retention behaviour of different soils and materials used in infiltration devices is determined with batch and column tests. Results of the laboratory tests are adsorption isotherms which represent input data for numerical transport modelling. The long term simulations are performed with combinations of different solutions (types of roof runoff) and infiltration devices (swale and trench) under different hydrogeological conditions. The presented results contain the infiltration of low polluted roof runoff, runoff from a roof with zinc sheets and from a roof with copper sheets concerning the heavy metals zinc, copper and lead. The increase of concentrations in the infiltration body is high. For the infiltrated water, the results show a migration to groundwater only for the low adsorbing soil.

Adsorption↗

PubMed2002

Release of algesic substances in human experimental muscle pain.

OBJECTIVE: We employed the 'delayed onset of muscle soreness' (DOMS) and the 'hypertonic saline' muscle pain models in combination with muscle microdialysis to evaluate the role of potentially algesic substances (lactate, glutamate, prostaglandin E2 (PGE2), nitric oxide (NO) and substance P (SP)) in the development of human muscle pain. METHODS: DOMS was induced by 2 sets of 50 concentric/eccentric contractions of the calf muscles 24 h before the start of microdialysis. During microdialysis pain was stimulated through calf muscle contractions (dorsal and plantar flexions of the foot). Hypertonic saline was injected into the biceps muscle (5 x 200 microl 5.8% NaCl, 2 min interval) during dialysis. The calf (no treatment) and biceps (normal saline) of the other side was used as control. RESULTS: Both models reliably induced muscle pain with similar intensities as assessed by visual analog scale. The DOMS exercise caused an increase of lactate in serum and the calf muscles of the DOMS leg. In addition, glutamate, PGE2 and substance P dialysate concentrations increased following contraction-induced pain stimulation (peak concentrations 125 +/- 20 microM, 239 +/- 45 pg/ml and 60 +/- 11 pg/ml for glutamate, PGE2 and SP, respectively). This increase did not occur in the control leg (peak concentrations 97 +/- 12 microM, 114 +/- 26 pg/ml and 46 +/- 9 pg/ml for glutamate, PGE2 and SP, respectively). Concentrations of nitric oxide were lower in the DOMS than control leg, particularly during the first 4h of microdialysis. Injection of hypertonic saline into the biceps muscle caused a significant increase of dialysate glutamate concentrations (peak 50 +/- 3 microM) whereas glutamate remained constant after injection of normal saline (mean 26 +/- 1 microM). Injection of hypertonic saline had no effect on lactate, PGE2 or NO levels. CONCLUSION: Our data support the notion that an inflammatory reaction may be involved in muscle soreness following eccentric exercise, whereas the injection of hypertonic saline into the muscle probably directly stimulates muscle nociceptors and causes glutamate release.

Adult↗

PubMed2002

Imatinib: a selective tyrosine kinase inhibitor.

The understanding of the pathophysiology of a large number of cancer types provides a strategy to target cancer cells with minimal effect on normal cells. Protein phosphorylation and dephosphorylation play a pivotal role in intracellular signaling; to regulate signal transduction pathways, there are approximately 700 protein kinases and 100 protein phosphatases encoded within the human genome. In cancer, as well as in other proliferative diseases, unregulated cell proliferation, differentiation and survival frequently results from abnormal protein phosphorylation. Although it is often possible to identify a single kinase that plays a pivotal role in a given disease, the development of drugs based upon protein kinase inhibition has been hampered by unacceptable side effects resulting from a lack of target selectivity. With the growing understanding of the molecular biology of protein tyrosine kinases and the use of structural information, the design of potential drugs directed towards the bind adenosine triphosphate (ATP)-binding site of a single target has become possible. These advances have transferred emphasis away from the identification of potent kinase inhibitors and more towards issues of target selectivity, cellular efficacy, therapeutic effectiveness and tolerability. In this paper, the relationship between molecular biology and drug discovery methods, as utilized for the identification of anticancer drugs, will be illustrated.

Adenosine Triphosphate↗

PubMed2001

A new structural class of selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

We describe the identification and in vitro characterization of a series of 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the 20S proteasome. Our initial SAR data demonstrate that the 2-aminobenzylstatine core structure can effectively serve as the basis for designing potent, selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

Amino Acids↗

PubMed2001

Modeling of the binding mode of a non-covalent inhibitor of the 20S proteasome. Application to structure-based analogue design.

The 2-aminobenzvlstatine derivative I is a 20S proteasome inhibitor of a novel chemical type identified by high throughput screening. The compound specifically inhibits the chymotrypsin-like catalytic activity of the human proteasome with an IC50 value in the micromolar range. Using the crystal structure of the yeast proteasome, we modeled the structure of the human proteasome in complex with 1. As one of the first applications of the model in our oncology programme targeting the proteasome, we designed an analogue of the inhibitor having enhanced stacking/hydrophobic interactions with the enzyme. One order of magnitude in inhibitory potency was gained.

Amino Acids↗

PubMed2001

Methylammonium groups at the solid walls of nanometer-sized, water-filled monolayer gaps as binding sites for a tetraanionic porphyrin.

Long-chain hydrosulfides containing two secondary amide functions and either electron-poor or electron-rich carbon-carbon double bonds were self-assembled on gold surfaces around a flat-lying, octaanionic porphyrin. Rigid and reactive surface monolayers with 2 nm-wide, porphyrin-based gaps were thus obtained. The gold electrodes were then immersed in water, and the double bonds on the gaps' surfaces reacted with methylamine. It was added to the double bonds either by Michael addition or by bromination with hypobromite followed by methylamine substitution. Only the double bonds at the border of the gaps were accessible to methylamine dissolved in the bulk water volume and could react. The walls of the rigid membrane gaps now contained methylammonium groups at the sites of the double bonds in defined heights. A tetracationic copper(II) porphyrinate could not diffuse any more into the gap and did not quench the fluorescence of the octaanionic porphyrin on the bottom of the gap. A tetraanionic porphyrin, on the other hand, was fixated by the ring of ammonium groups. The bound porphyrin then acted as molecular cover for the gap with respect to ferricyanide transport from bulk water to the electrode. It was removed by raising the pH to a value of 12, where the methylammonium groups were neutralized to amines. Lowering the pH to 7 again and addition of more of the anionic porphyrin reclosed the gap.The porphyrin "cover" should be localized at distances of 8-10 and 20 A from the bottom porphyrin by multiple charge interactions. The 8-10 A distance is ideal for studies of photoinduced electron transfer between two porphyrin monomers of different redox potential. Furthermore it was found, that redox-active tyrosine could be trapped in the water volume above the porphyrin on gold.

Journal Article↗

PubMed2001

Proteasome- and p38-dependent regulation of ERK3 expression.

Proteasome inhibition leads to accumulation of transcription factors, heat shock proteins, cyclins, and other proteasome substrate proteins by blocking their proteolytic degradation. An increase in gene transcription upon proteasome inhibition was found for a group of proteins, including p21(WAF1/CIP1), ubiquitin, and transcription factors. In this study, we have demonstrated selective up-regulation of extracellular signal-regulated kinase 3 (ERK3) mRNA and protein expression upon treatment with peptide-based proteasome inhibitors or lactacystin. ERK3 is a family member of the mitogen-activated protein kinases (also called ERK) that are key mediators of signal transduction from the cell surface to the nucleus. ERK3 up-regulation is independent of the p53, Bcl2, and caspase 3 status of cells. p38 pathway kinase inhibitors prevent proteasome-dependent ERK3 induction and enhance the antiproliferative effect of proteasome inhibitors. MCF-7 cells expressing ERK3 ectopically show increased resistance toward proteasome inhibition. The results indicate that ERK3 expression is a consequence of p38 pathway activation and most probably represents an intracellular defense or rescue mechanism against cell stress and damage induced by proteasome inhibition.

Cysteine Endopeptidases↗

PubMed2001

Tyrosine kinase inhibitors: from rational design to clinical trials.

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.

Animals↗

PubMed2001

Local field enhancement effects for nanostructuring of surfaces.

We report on a method that allows the nanostructuring of surfaces with intense laser pulses. For this purpose isolated polystyrene spheres with diameters in the order of the laser wavelength were deposited on a silicon or glass surface. Illumination with short and ultrashort laser pulses produced holes underneath these particles. Calculations of the field near the particles make clear that geometrical optics, that is, focusing by a spherical lens, as well as near-field effects, contribute to the size and shape of these holes. This technique can be utilized for the parallel structuring of large surface areas with a single laser shot.

Journal Article↗

PubMed2001

[Chances in surgical treatment of bronchial carcinoma under palliative conditions].

UNLABELLED: Palliative surgery aims at symptomatic relief in patients in whom curative therapy seems not feasible. When diagnostic imaging techniques describe advanced stage IIIa, IIIb or IV malignancy, despite of palliative intention curative resection may still be possible. Objective of the present study was to investigate lung cancer patients undergoing surgery with palliative intent and to compare their prognosis with patients whose tumor resection had been complete (R0) or incomplete (R1/R2). PATIENTS AND METHOD: Patients were assigned to one of the three groups on the basis of the following criteria: palliative intention with subsequent complete resection (group I, n = 11); curative intention with subsequent incomplete resection (group II, n = 38), palliative intention with incomplete resection (group III, n = 23). Additionally 3 patients were operated on by explorative thoracotomy. A total number of 75 patients was therefore investigated. Median follow-up period was 34.5 months. Survival rates were calculated using the Kaplan-Meier method. RESULTS: The following procedures involving resection of pulmonary tissue were performed: pneumonectomy (n = 10), extended pneumonectomy (n = 32), lobectomy (n = 5), extended lobectomy (n = 11), sleeve lobectomy (n = 7), bilobectomy (n = 3), extended bilobectomy (n = 4). The 30 days hospital mortality rate was 13%. Median survival times were 25.5 months in group I, 12.8 months in group II and 7.7 months in group III (statistical significance: group I vs. group II/III, p < 0.05). CONCLUSIONS: Results of the present study show that patients with bronchial carcinoma in advanced tumor stages III and IV may still benefit from pulmonary resection, particularly when reduction of their somatic complaints is considered. In 11 patients, R0 resection was feasible leading to a statistically significant prolongation of their survival rates.

Adenocarcinoma↗

PubMed2001

DNA polynucleotide probes generated from representatives of the genus Acinetobacter and their application in fluorescence in situ hybridization of environmental samples.

The application of rRNA directed polynucleotide probes carrying multiple labels facilitates the detection of target cells by fluorescence in situ hybridizations and allows specific enrichment by cell fishing. So far, exclusively RNA transcript probes have been used. To reduce the effort in the preparation of the polynucleotides and to enhance their stability, DNA probes matching a part of the highly variable domain III on the 23S rRNA were constructed by amplification of the target region using PCR. Fluorescent labeling was achieved by incorporation of Cy3-labeled desoxyribonucleotides in the amplification. DNA polynucleotide probes were constructed for the seven validly described Acinetobacter species. Amplified domain III rDNA of A. baumannii and A. calcoaceticus could be readily applied as species specific probe. In addition, rDNA fragments could be used to recognize two groups of species, one comprising A. haemolyticus, A. junii and A. radioresistens and the other one A. lwoffii and A. johnsonii. Acinetobacter baumannii cells, some of them occurring in filaments, could be detected by in situ hybridization in native samples of activated sludge.

Acinetobacter↗

PubMed2000

Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1.

The ubiquitin/proteasome pathway has been implicated in a wide variety of cellular processes and the number of substrates degraded by the proteasome is impressive. Most prominently, the stability of a large number of transcription factors is regulated by ubiquitination. To elucidate pathways regulated by the proteasome, gene expression profiles were generated, comparing changes of mRNA expression of 7900 genes from the UniGene collection upon exposure of cells to the proteasome inhibitors Lactacystin, Lactacystin-beta-lactone or MG132 by means of microarray based cDNA hybridization. The three profiles were very similar, but differed significantly from a gene expression profile generated with the histone deacetylase inhibitor Trapoxin A, indicating that the observed alterations were indeed due to proteasome inhibition. Two of the most prominently induced genes encoded the growth arrest and DNA damage inducible protein Gadd153 and the activating transcription factor ATF3, both transcription factors of the CCAAT/enhancer binding protein (C/EBP) family. A third gene encoded for the transcriptional repressor and c-Myc antagonist Mad1. Our results suggest that proteasome inhibition leads to upregulation of specific members of transcription factor families controlling cellular stress response and proliferation. Oncogene (2000).

Base Sequence↗

PubMed2000

Structure-based design of potent CDK1 inhibitors derived from olomoucine.

Cyclin-dependent kinase 1 (CDK1), an enzyme participating in the regulation of the cell cycle, constitutes a possible target in the search for new antitumor agents. Starting from the purine derivative olomoucine and following a structure-based approach, potent inhibitors of this enzyme were rapidly identified. The molecular modeling aspects of this work are described.

Amino Acid Sequence↗