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Biomedical subjects

W Eberhardt

Publications and source records attributed to W Eberhardt.

At least 19 recordsLinked to original sources
PubMed2002

Ferromagnetism in one-dimensional monatomic metal chains.

Two-dimensional systems, such as ultrathin epitaxial films and superlattices, display magnetic properties distinct from bulk materials. A challenging aim of current research in magnetism is to explore structures of still lower dimensionality. As the dimensionality of a physical system is reduced, magnetic ordering tends to decrease as fluctuations become relatively more important. Spin lattice models predict that an infinite one-dimensional linear chain with short-range magnetic interactions spontaneously breaks up into segments with different orientation of the magnetization, thereby prohibiting long-range ferromagnetic order at a finite temperature. These models, however, do not take into account kinetic barriers to reaching equilibrium or interactions with the substrates that support the one-dimensional nanostructures. Here we demonstrate the existence of both short- and long-range ferromagnetic order for one-dimensional monatomic chains of Co constructed on a Pt substrate. We find evidence that the monatomic chains consist of thermally fluctuating segments of ferromagnetically coupled atoms which, below a threshold temperature, evolve into a ferromagnetic long-range-ordered state owing to the presence of anisotropy barriers. The Co chains are characterized by large localized orbital moments and correspondingly large magnetic anisotropy energies compared to two-dimensional films and bulk Co.

Journal Article↗
PubMed2002

Photon-induced thermal desorption of CO from small metal-carbonyl clusters.

Thermal CO desorption from photoexcited free metal-carbonyl clusters has been resolved in real time using two-color pump-probe photoelectron spectroscopy. Sequential energy dissipation steps between the initial photoexcitation and the final desorption event, e.g., electron relaxation and thermalization, have been resolved for Au2(CO)(-) and Pt2(CO)5-. The desorption rates for the two clusters differ considerably due to the different numbers of vibrational degrees of freedom. The unimolecular CO-desorption thresholds of Au2(CO)(-) and Pt2(CO)5- have been approximated by means of a statistical Rice-Ramsperger-Kassel calculation using the experimentally derived desorption rate constants.

Journal Article↗
PubMed2002

Induction chemotherapy followed by concurrent chemotherapy and definitive high-dose radiotherapy for patients with locally advanced non-small-cell lung cancer (stages IIIa/IIIb): a pilot phase I/II trial.

BACKGROUND: Overall prognosis of patients with locally advanced non-small-cell lung cancer (LAD-NSCLC) is still unfavourable. Different attempts to improve treatment results have been made using combinations of chemotherapy and radiotherapy. The aim of this pilot phase I/II investigation was to test the feasibility and toxicity of a definitive multimodality protocol in patients with irresectable NSCLC stages IIIA (N2) and IIIB. PATIENTS AND METHODS: Thirty LAD-NSCLC patients (stages IIIA/IIIB: 3/27; median age: 54 years, range 34-70; male/female: 17/13) who were consecutively enrolled onto our ongoing neoadjuvant multimodality protocol from October 1996 to February 1999 remained inoperable after induction treatment. Three cycles of cisplatin/etoposide (PE) were followed by hyperfractionated accelerated radiotherapy (HF-RTx: 1.5 Gy bid up to a total dose of 45 Gy in 3 weeks) concurrent with one cycle of PE. Definitive local treatment was completed with a small volume boost of 20 Gy (qd), adding up to a total dose of 65 Gy to the primary. Patients were routinely offered prophylactic cranial irradiation (PCI; 30 Gy; 2 Gy qd). RESULTS: Overall toxicity of the definitive CTx/RTx protocol-the main endpoint of this investigation-turned out to be acceptable (oesophagitis grade 3/4: 6/4 patients; pneumonitis grade 3/4: 0/1 patients; no treatment-related deaths). Actuarial survival at 2 years was 31% with a loco-regional control rate of 21%. CONCLUSIONS: This regimen turned out to be feasible with acceptable toxicity and will serve as a reference arm in a planned randomised trial in stage IIIB NSCLC, testing the value of surgery in this setting: preoperative induction CTx/RTx followed by surgery versus definitive CTx/RTx.

Adult↗
PubMed2001

Downregulation of integrin-linked kinase mRNA expression by nitric oxide in rat glomerular mesangial cells.

Inflammatory glomerular diseases are accompanied by changes in the expression patterns of growth factors, mediators and matrix-associated proteins in mesangial cells and by the production of nitric oxide via the cytokine-inducible form of the nitric oxide synthase. Nitric oxide has been shown to act potently on gene transcription. To identify genes that are differentially expressed by endogenously produced nitric oxide, we forced rat mesangial cells to produce high amounts of nitric oxide by exposure to inflammatory cytokines and compared the mRNA expression patterns of cytokine-stimulated mesangial cells with cells that were additionally treated with the nitric oxide synthase inhibitor L-NMMA to block endogenous NO synthesis. We used a modification of a low stringency RT-PCR approach designated as RNA arbitrarily-primed polymerase chain reaction (RAP-PCR). In this way, we identified among others the integrin-linked kinase (ILK) as an NO-regulated gene. The NO-mediated changes in the mRNA and protein expression patterns of ILK were compared to that of "secreted protein acidic and rich in cystein" (SPARC), a gene that was identified as NO-regulated in the same set of experiments (Walpen et al., J. Am. Soc. Nephrol., 11, 468-476). ILK and SPARC mRNA levels by were downregulated by cytokines via endogenously produced nitric oxide in a comparable manner as verified by Northern blot analysis. In contrast, cytokine- induced NO production or administration of exogenous NO-donors strongly reduced SPARC protein levels without altering ILK protein content in mesangial cells over a period up to 72 hours. Blocking de novo protein synthesis showed a short halflife of SPARC (< 2 hours) whereas ILK-protein was stable over a period of 7 hours, indicating that NO-mediated reduction of ILK mRNA levels does not influence protein content of ILK in mesangial cells under the time limitations given under cell culture conditions. However, a role for cytokines/NO in ILK-long-term regulation in chronic inflammatory diseases that may influence phenotypic responses such as apoptosis or cell proliferation remains to be elucidated.

Animals↗
PubMed2001

Nitric oxide and mechanisms of redox signalling: matrix and matrix-metabolizing enzymes as prime nitric oxide targets.

One of the greatest biomedical breakthroughs of the twentieth century was the discovery of endothelium-derived relaxing factor and its identification as nitric oxide (NO). NO has received special attention ever since: besides its potent vasodilatory and vasoprotective effects, NO was identified as a key player in innate immunity and was found to act as an unconventional type of neurotransmitter. This article focuses on mechanisms of NO signalling that form the basis of functional cell responses to accommodate changes in the cellular microenvironment. Redox-based regulation of signal transduction and, on a more long-term scale, changes in gene expression will be exemplified by NO-modulation of matrix components and matrix-metabolizing enzymes. It seems to be a safe bet that ongoing analyses of NO signalling and gene expression will provide a wealth of promising therapeutic targets in human diseases.

Animals↗
PubMed2001

Nitric oxide induces MIP-2 transcription in rat renal mesangial cells and in a rat model of glomerulonephritis.

Nitric oxide is a crucial mediator of several forms of glomerulonephritis. We examined the effects of NO on the mRNA expression pattern in glomerular mesangial cells by using a low-stringency reverse transcriptase-polymerase chain reaction method and detected a cDNA fragment that was induced by interleukin 1b (IL-1b) and further up-regulated by the NO donor diethylenetriamine-nitric oxide (DETA-NO). Each respective cDNA fragment was found to match with the cDNAs of rat macrophage inflammatory protein 2 (MIP-2) and GRO/cytokine-induced neutrophil chemoattractant 2b (CINC-2b). Further characterization of MIP-2 regulation by Northern blot analysis confirmed an NO- and IL-1b-dependent increase in MIP-2 mRNA levels. Moreover, inhibition of IL-1b-induced endogenous NO formation by the NO-synthase (NOS) inhibitor L-NMMA markedly attenuated MIP-2 protein expression. We cloned 770 bp of the 5'-flanking region of rat MIP-2 and fused this fragment to a luciferase reporter gene. Transfection of the construct into mesangial cells resulted in a 3.5-fold increase in luciferase activity in cells treated with DETA-NO when compared to controls, suggesting a transcriptional mechanism for NO-induced MIP-2 expression. Deletion and mutational analysis identified critical nuclear factor (NF)-kB and NF-IL-6 binding sites required for NO regulation of MIP-2. In vivo, inhibition of NO synthesis in the Thy-1.1 model of mesangioproliferative glomerulonephritis by the specific inducible-NOS inhibitor L-NIL resulted in a marked reduction of MIP-2 mRNA expression. Furthermore, infiltration of neutrophils into the glomerulus was dramatically attenuated in L-NIL-treated rats.

Amidines↗
PubMed2001

Regulation of gene expression by nitric oxide.

Nitric oxide (NO) modulates transcription factors that bind specific cis-regulatory DNA responsible for coordinating the spatial and temporal patterns of gene expression that are initiated by a changing microenvironment. In this way NO helps to orchestrate gene transcription and forms the basis of functional cell responses to accommodate metabolic requirements and to coordinate endogenous defense mechanisms against a variety of stress and disease conditions. There is marked overlap between the signalling pathways triggered by NO, superoxide, and hypoxia. Understanding the redox-based regulation of signal transduction and gene expression will provide insights into how cell activities are constantly coordinated and how promising new therapies may be developed.

Animals↗
PubMed2001

Preoperative treatment strategies in stage III non-small cell lung cancer.

Recent experience has emphasized the need to include systemic chemotherapy in combined-modality management of locally advanced non-small cell lung cancer stage III. If definitive surgery is planned in these situations, preoperative application of drugs-induction chemotherapy-has many advantages in comparison to postoperative delivery. Patients' compliance to treatment, achievable dose intensities of drugs, possible locoregional downstaging, and frequent postoperative problems following complex resections are some of the arguments favouring preoperative chemotherapy. Despite numerous phase-II investigations, little evidence from randomized phase-III trials has been generated. Early inclusion of radiotherapy prior to definitive resection may help to improve preoperative downstaging. Besides available mature phase-II data, phase-III results from ongoing randomized trials are lacking to define the overall value of such a complex approach. Important issues in the future will aim at individualizing these intensive programs according to findings in clinical prognostic factor analyses and to prospectively validate a prognostic risk stratification. Data from translational and molecular research may further help to develop such evidence-based guidelines.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

[Neoadjuvant chemotherapy and chemoradiotherapy in surgically treated non-small-cell stage III bronchial carcinoma].

Patients with unfavorable stages of lung cancer are rarely cured with local treatment modalities alone. Aim of our phase II trial was to investigate the effectivity of a multimodality treatment. Ninety-four patients with NSCLC (stage IIIA/IIIB) were treated preoperatively with chemoradiotherapy (cisplatin and etoposide, 45 Gy hyperfractionated accelerated radiotherapy). After repeat mediastinoscopy patients underwent surgery. Complete resection (R0) was achieved in 53% of all patients with NSCLC. Two patients died of sepsis preoperatively and four postoperatively (90-days lethality: 6.4%). The median survival time was 20 months for IIIA and 18 months for IIIB. Calculated survival rates at 6 years were 34% for IIIA and 17% for IIIB. This multimodality treatment demonstrates high efficacy in prognostically unfavorable NSCLC compared with historical controls.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways.

The modulation of cell signaling by free radicals is important for the pathogenesis of inflammatory diseases. Recently, we have shown that NO reduces IL-1beta-induced matrix metalloproteinase (MMP-9) expression in glomerular mesangial cells (MC). Here we report that exogenously administrated superoxide, generated by the hypoxanthine/xanthine oxidase system (HXXO) or by the redox cycler 2, 3-dimethoxy-1,4-naphtoquinone, caused a marked amplification of IL-1beta-primed, steady state, MMP-9 mRNA level and an increase in gelatinolytic activity in the conditioned medium. Superoxide generators alone were ineffective. Cytokine-induced steady state mRNA levels of TIMP-1, an endogenous inhibitor of MMP-9, were affected similarly by HXXO. Transient transfection of rat mesangial cells with 0.6 kb of the 5'-flanking region of the rat MMP-9 gene proved a transcriptional regulation of MMP-9 expression by superoxide. HXXO augmented the IL-1beta-triggered nuclear translocation of p65 and c-Jun and, in parallel, increased DNA binding activities of NF-kappaB and AP-1. Mutation of either response element completely prevented MMP-9 promoter activation by IL-1beta. Moreover, specific inhibitors of the classical extracellular signal-regulated kinase (ERK) pathway and p38 mitogen-activated protein kinase (MAPK) cascade, partially reversed the HXXO-mediated effects on MMP-9 mRNA levels, thus demonstrating involvement of ERKs and p38 MAPKs in MMP-9 expression. Furthermore, IL-1beta-triggered phosphorylation of all three MAPKs, including p38-MAPK, c-Jun N-terminal kinase, and ERK, was substantially enhanced by superoxide. Our data identify superoxide as a costimulatory factor amplifying cytokine-induced MMP-9 expression by interfering with the signaling cascades leading to the activation of AP-1 and NF-kappaB.

Adjuvants, Immunologic↗
PubMed2000

One-dimensional spin-polarized quantum-wire states in Au on Ni(110)

Au chain structures have been prepared on Ni(110). Au6 s,p-derived features in photoemission spectra are identified as quantum-wire states due to their strong dispersion along the chains and absence of dispersion perpendicular to the chains in agreement with our ab initio calculation of the electronic structure. Spin analysis reveals that the states have minority-spin character showing that the confinement of electrons in the chain structure depends on the electron spin.

Journal Article↗
PubMed2000

Ultrafast hot-electron dynamics observed in Pt( -)(3) using time-resolved photoelectron spectroscopy

Time-resolved two-photon photoelectron spectra have been measured for free Pt( -)(3) using femtosecond pulses of 1.5 eV photon energy in a pump-probe configuration. The time-dependent photoelectron distribution reveals a lifetime of optically excited states of less than 70 fs. Such an unexpected fast electron relaxation in Pt( -)(3) suggests the existence of inelastic electron-electron scattering processes in a triatomic cluster which result in a lifetime similar to those of bulk metals.

Journal Article↗
PubMed2000

Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human lung cancer cell lines.

PURPOSE: Modulation of DNA repair represents one strategy to overcome cellular drug resistance to alkylating agents and platinum compounds. The effects of different known DNA repair modulators such as O6-benzylguanine (6 microg/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 microg/ml) and methoxamine (12.4 microg/ml) on the cytotoxicity of mafosfamide, chlorambucil, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin and carboplatin were tested in human lung cancer cell lines. METHODS: Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin-resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P and its cisplatin-resistant counterpart L23/CPR were evaluated by the MTT colorimetric assay. RESULTS: O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA alkyltransferase, significantly sensitised MOR/P and MOR/CPR cells to the cytotoxic effect of BCNU. Fludarabine, methoxamine and aphidicolin did not change the chemosensitivity of the parental and cisplatin-resistant cell lines to any cytotoxic drug tested. Interestingly, O6-benzylguanine enhanced the chemoresistance of parental and cisplatin-resistant cell lines to platinum compounds. Also, pentoxifylline increased resistance of the MOR cell lines to mafosfamide. CONCLUSIONS: Modulation of DNA repair elicits not only chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.

Antineoplastic Agents, Alkylating↗
PubMed2000

Inhibition of NFkappaB-mediated pro-inflammatory gene expression in rat mesangial cells by the enolized 1,3-dioxane-4, 6-dione-5-carboxamide, CGP-43182.

1. CGP-43182 has been described as a potent inhibitor of group IIA secreted phospholipase A(2) (group IIA sPLA(2)) activity in vitro. In rat mesangial cells, inhibition of group IIA sPLA(2) activity by CGP-43182 results in a 70% reduction of cytokine-stimulated prostaglandin E(2) biosynthesis, suggesting that group IIA sPLA(2) participates in arachidonic acid release and eicosanoid formation. Under these conditions the cytosolic phospholipase A(2) is not affected. 2. In mesangial cells, in addition to inhibition of catalytic activity, the membrane-permeant CGP-43182 completely blocked interleukin 1beta (IL1beta)-stimulated group IIA sPLA(2) gene expression. 3. A further action of CGP-43182 was a complete inhibition of cyclo-oxygenase-2 gene expression, resulting in a drastic reduction of prostaglandin formation in mesangial cells. 4. Moreover, CGP-43182 completely blocked IL1beta-induced gene expression of the inducible nitric oxide synthase, leading to an inhibition of cytokine-stimulated nitric oxide formation. 5. In contrast, the stimulatory effect of the cell-permeant cyclic AMP-analogue, dibutyryl-cAMP, on the induction of these enzymes was not inhibited by CGP-43182. These data indicate that CGP-43182 interferes with IL1beta- but not cyclic AMP-activated transcriptional regulation. 6. By studying components of the upstream transcription machinery, we observed an inhibition of NFkappaB activation by CGP-43182 in IL1beta-treated cells. Moreover, we observed that CGP-43182 prevented the phosphorylation and proteolytic degradation of the endogenous NFkappaB inhibitor, IkappaB, a process necessary for NFkappaB activation. 7. From our data, we propose that CGP-43182 is a potent anti-inflammatory drug useful for preventing the consequences of a concerted action of cytokine-stimulated pro-inflammatory genes mediated by NFkappaB.

Animals↗
PubMed2000

Nitric oxide modulates expression of matrix metalloproteinase-9 in rat mesangial cells.

UNLABELLED: Nitric oxide modulates expression of matrix metalloproteinase-9 in rat mesangial cells. BACKGROUND: High-output levels of nitric oxide (NO) are produced by rat mesangial cells (MCs) in response to proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) by the inducible isoform of NO synthase (iNOS). We tested modulatory effects of NO on the expression and activities of matrix metalloproteinases-9 and -2 (MMP-9 and MMP-2), respectively. Temporal and spatial expression of these MMPs and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), seems to be critical in the extensive extracellular matrix (ECM) remodeling that accompanies sclerotic processes of the mesangium. Methods and Results. Using the NO donors S-Nitroso-N-acetyl-D,L-penicillamine (SNAP) and DETA-NONOate, we found strong inhibitory effects of NO mainly on the IL-1beta-induced MMP-9 mRNA levels. NO on its own had only weak effects on the expression of MMP-9 and MMP-2. The addition of the NOS inhibitor NG-monomethyl L-arginine (L-NMMA) dose dependently increased steady-state mRNA levels of cytokine-induced MMP-9, suggesting that endogenously produced NO exerts tonic inhibition of MMP-9 expression. MMP-9 activity in conditioned media from MCs costimulated with IL-1beta and NO donor contained less gelatinolytic activity than media of cells treated with IL-1beta alone. Exogenously added NO did not alter gelatinolytic activity of MMP-9 in cell-free zymographs. The expression levels of TIMP-1 were affected by NO similarly to the expression of MMP-9. CONCLUSION: We conclude that NO modulates cytokine-mediated expression of MMP-9 and TIMP-1 in rat MCs in culture. Our results provide evidence that NO-mediated attenuation of MMP-9 gelatinolytic activity is primarily due to a reduced expression of MMP-9 mRNA, and not the result of direct inhibition of enzymatic activity.

Animals↗
PubMed2000

Combined modality therapy in NSCLC.

Combined modality treatment has 'come out of age' and increasingly represents standard of care for a rapidly growing number of patients in locally advanced stages of NSCLC. Modern progress of treatment techniques as well as possibilities for supportive interventions will lead to lesser treatment toxicities, better patient's compliance to treatment protocols and combinations of different modalities with a more efficient outcome. This number will further increase, as more and more centres in Europe are setting up the logistics of multidisciplinary treatment groups for patients with lung cancer. Standard of care for most disease stages is currently under investigation in large randomised phase-III trials. Further research in the forthcoming years has to address questions of treatment individualisation (risks, prognosis, need for local control in the individual patient, biological evaluation of tumour aggressiveness, DNA-fingerprinting of tumours, evaluation of MRD-status, treatment in the community). New drugs or treatment principles with different mechanisms of action such as antiangiogenesis factors, signal-transduction inhibitors, immunotherapy, antisense-oligonucleotides or gene(replacement) therapy may stimulate further clinical research. This may eventually define 'new modalities of treatment' thus leading to modern 'second-generation combined-modality protocols' including some of the new principles.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Failure of potassium siphoning by Müller cells: a new hypothesis of perfluorocarbon liquid-induced retinopathy.

PURPOSE: To determine the effect of perfluorocarbon liquid (PFCL)-induced abolition of potassium siphoning by the vitreal end feet of Miller cells. METHODS: Porcine eyecups were filled with stained balanced salt solution and PFCLs (perfluorodecalin, perfluorooctane, perfluoroperhydrophenanthrene or the semifluorocarbon perfluorohexylhexane). With optical coherence tomography, the distance between PFCL and retina was determined, and the size of the aqueous space covering the retinal surface was estimated. The data were used to calculate the retinal potassium siphoning into small aqueous volumes. RESULTS: The distance between PFCL and retinal surface was found to be less than 5 to 10 microm with any PFCL tested. The resultant volume of the aqueous space was too small to act as a sufficient sink for K+ ion siphoning. CONCLUSIONS: A certain threshold volume of vitreal fluid seems to be necessary for efficient buffering of intraretinal increases of K+ and perhaps other (e.g., H+) ions through the Müller cells. When the aqueous fluid is replaced by a PFCL (or by silicone oil) for longer periods, the outer retina becomes subject to long-lasting K+ accumulation, and consequent neurodegeneration and reactive gliosis occurs. The authors propose to search for new vitreous-substituting fluids with the capability to dissolve ions.

Animals↗