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Biomedical subjects

W Eberhardt

Publications and source records attributed to W Eberhardt.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells.

To characterize mechanisms which may determine the fate of apoptotic cells, we investigated chemokine expression in apoptotic promonocytic U937 cells or peripheral blood mononuclear cells (PBMC). Exposure of U937 cells to etoposide (VP-16) or the nitric oxide (NO) donor DETA-NO, both inducers of apoptosis in these cells, was associated with increased expression of the chemokines IL-8 and macrophage inflammatory protein-1 alpha. Up-regulation of IL-8 mRNA expression by VP-16 or DETA-NO was observed as early as 4 h or 6 h, respectively, after onset of treatment and was still detectable after 19 h of exposure. A serine protease inhibitor prevented both VP-16-induced apoptosis and release of IL-8, whereas inhibition of p38 MAP kinases reduced IL-8 secretion only. Moreover, we observed that incubation with 2-chlorodeoxyadenosine (CdA) up-regulated release of IL-8 from adherent PBMC in parallel to induction of apoptosis. In these cells a modest but significant induction of TNF-alpha release by CdA was also detected. In addition, CdA augmented release of IL-8 from whole blood cultures. By facilitating adequate recruitment of phagocytes to sites of cell death, stress-induced up-regulation of chemokines associated with apoptosis may contribute to mechanisms aiming at efficient removal of apoptotic cells.

Apoptosis↗
PubMed1999

Preoperative chemoradiotherapy and surgery for selected non-small cell lung cancer IIIB subgroups: long-term results.

BACKGROUND: Preoperative chemoradiotherapy is feasible for selected patients with non-small cell lung cancer stage IIIb. The aim of this investigation was to analyze long-term results after this multimodality approach and to identify subgroups with improved long-term prognosis. METHODS: From March 1991 to June 1996, 56 patients were entered. Three cycles of cisplatin (P) (60 mg/m2, days 1 + 7) and etoposide (E) (150 mg/m2, days 3 to 5 qd 22) were followed by one cycle of radiotherapy/chemotherapy (RTx/CTx) (45 Gy, 1.5 Gy bid/3 weeks with P 50 mg/m2 days 2 + 9/E 100 mg/m2 days 4 to 6) followed by repeat mediastinoscopy and surgery. RESULTS: There were 46 men and 10 women (age 34 to 69 years, median 55 years; World Health Organization status 0 to 2, median 1). Twenty-eight had T4, and 32 had proven N3, in detail: T4N0/1, 10; T4N2, 14; T3N3, 9; T4N3, 4; and T1/2N3, 19. Thirty-four (61%) were operated on; 27 (48%) were completely (R0) resected. Survival at 5 years is 26% for all, and 43% for R0 patients. Toxicity included two deaths (one septicemia, one anastomosis insufficiency). CONCLUSIONS: This intensive program proved to be highly effective in unfavorable IIIB subgroups with promising long-term survival for T4 tumors as well as N3 disease.

Adult↗
PubMed1999

Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: long-term results of a phase II trial.

Following mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22, IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52 months (30+ - 75+). Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

Adolescent↗
PubMed1999

Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects.

PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.

Adult↗
PubMed1999

Inducible NO synthase: role in cellular signalling.

The discovery of endothelium-derived relaxing factor and its identification as nitric oxide (NO) was one of the most exciting discoveries of biomedical research in the 1980s. Besides its potent vasodilatory effects, NO was found under certain circumstances to be responsible for the killing of microorganisms and tumour cells by activated macrophages and to act as a novel, unconventional type of neurotransmitter. In 1992, Science picked NO as the 'Molecule of the Year', and over the past years NO has become established as a universal intercellular messenger that acutely affects important signalling pathways and, on a more long-term scale, modulates gene expression in target cells. These actions will form the focus of the present review.

Animals↗