Biomedical subjects

W Meier

Publications and source records attributed to W Meier.

At least 37 records · Page 2Linked to original sources

PubMed2000

20q13 and cyclin D1 in ovarian carcinomas. Analysis by fluorescence in situ hybridization.

In ovarian carcinomas, alterations of the chromosomal region 20q13 and the cyclin D1 gene have been described. This study has sought to determine their prognostic significance. Fluorescence in situ hybridization (FISH) on dissociated nuclei and paraffin sections with DNA probes for 20q13.2 and cyclin D1, as well as immunohistochemistry (cyclin D1), were applied to formalin-fixed tissue of 69 invasive ovarian carcinomas, mainly of serous type. On dissociated nuclei 33/47 cases (70%) and on tissue sections 13/66 cases (20%) demonstrated an increase of 20q13.2 copies. The presence of > or =4 copies per nucleus (isolated nuclei) and > or =3 copies per nucleus (sections) was associated with an adverse prognosis (Kaplan-Meier for FIGO stage III after stratification for residual tumour: p=0.0049 and p=0.03, respectively). Thirty-four out of 47 cases (72%) showed an increase of cyclin D1 copies. Kaplan-Meier analysis for FIGO stage III after stratification for residual tumour>2 cm or < or =2 cm revealed an unfavourable outcome for cases with more than two cyclin D1 copies (p=0.04). No correlation was seen between FISH and immunohistochemistry. Multivariate analysis identified residual tumour (p=0.0002), 20q13.2 gain (p=0.0004) and cyclin D1 gain (p=0.0343) as independent prognostic factors. It is concluded that gains of chromosomal region 20q13.2 and the cyclin D1 gene are frequent and biologically important events, with prognostic relevance, in advanced ovarian carcinomas.

Adult↗

PubMed2000

Nonylphenol affects the granulation pattern of epidermal mucous cells in rainbow trout, Oncorhynchus mykiss.

Nonylphenol is a biodegradation product of nonionic surfactants and has recently attracted considerable attention due to its estrogenic potential. Sexually mature male rainbow trout were repeatedly exposed (one to four periods of 10 days each) to environmentally relevant concentrations of nonylphenol (1 microg/L, 10 microg/L) and for comparison, trout were injected with estradiol. Since estrogens are known to induce structural changes within the fish skin, a similar effect of xenobiotics with estrogen-like activity was assumed. Samples of skin were evaluated by means of light and electron microscopy and histochemistry. In trout exposed to nonylphenol and to estradiol, the structure of the epidermis was altered: an irregular overall architecture was often accompanied by detached pavement cells, vacuolation of the cytoplasm, and severely deformed cell nuclei. However, the granulation pattern of the mucous cells was influenced exclusively after exposition to nonylphenol. The number of large and irregularly shaped mucosomes depended more on the exposure period than on the concentration of nonylphenol. Furthermore, this alteration has not yet been reported for any other pollutant or stressor and, thus, can be classified as an effect that would strongly indicate exposure to nonylphenol.

Animals↗

PubMed2000

Surface tension and viscosity of surfactant from the resonance of an oscillating drop.

The oscillating drop surfactometer (ODS) measures surface tension (gamma) and energy dissipation (damping constant b) of surfactant on a 1 microl sample. gamma is obtained from the period of oscillation and b from its free decay or from the phase shift slope in resonance. After calibration with substances with different gamma, corrections were made for capillary fixation and loss of mass by evaporation. Surface active substances are delivered from liposomes in the interior (subphase) or injected from outside, with microdrops (180 pl each) of solution. As an application example, we have investigated surfactant extract and pure phospholipid. In minutes after formation of a drop containing a diluted Survanta suspension, gamma, decreases by 20 mN/m, while b increases three-fold. This effect, assigned to spontaneous adsorption from liposomes to the surface, is not seen with pure dipalmitoylphosphatidylcholine (DPPC) under our conditions. However, microdrop injection of DPPC triggers a rapid decrease of gamma and a delayed strong increase in b. The effect is modulated by DPPC in the subphase and by cholesterol. Investigations with L-alpha-lysophosphatidylcholine show the high sensitivity of the ODS technique in the determination of the energy dissipation at air-liquid boundary surfaces. Although the ODS is limited to applications with gamma > 15 mN m(-1), it offers the advantage to give, with small samples and within seconds, a simultaneous readout of both Surface tension gamma and the parameter b, as a measure of surface viscosity.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2000

Immunohistochemical analysis of drug resistance-associated proteins in ovarian carcinomas.

Loss of function of the tumor suppressor gene p53, increased expression of glutathione-S-transferase pi (GST7pi) and the major vault protein are involved in drug resistance of ovarian carcinomas. However, a study comparing these factors has not yet been performed. Therefore, paraffin-embedded material of 213 ovarian tumors with well-documented follow-up was used for immunohistochemical analysis of p53 protein, GSTpi, and major vault protein (antibodies LRP-56, LMR-5). Forty-six percent of the cases showed nuclear p53 accumulation. Strong immunoreactivity for GSTpi, LRP-56, and LMR-5 was seen in 50%, 36%, and 47%, respectively. p53 positivity was most often found in serous carcinomas (p < 0.05). Strong GSTpi expression was the only factor that correlated with clinical resistance to chemotherapy (p = 0.04). In the whole group, as well as in FIGO III cases stratified for residual disease < or = and >2 cm, p53 and GSTpi correlated with an adverse outcome (p = 0.01 for p53 and p = 0.04 for GSTpi). Strong LRP-56 or LMR-5 staining was associated with a tendency towards poorer prognosis, without reaching statistical significance. In multivariate analysis for FIGO III, only residual disease and p53 proved to be independent prognostic factors. Our observations confirm the prognostic significance of p53 accumulation in ovarian carcinomas. Only GSTpi immunoreactivity was significantly correlated with drug resistance.

Adenocarcinoma, Mucinous↗

PubMed2000

[Anthracyclines in therapy of ovarian carcinoma: a systematic review of primary and 2nd-line therapy after platinum].

Despite being the subject of clinical research for more than 20 years, the role of anthracyclines in the treatment of ovarian cancer is still undefined. This review summarizes and re-evaluates the published data with the anthracylines doxorubicin, epirubicin (4'-epi-doxorubicin), daunorubicin (idarubicin), aclarubicin, and pirarubicin. The studies were identified by MEDLINE-search and analysis of the references cited in the identified articles and reviews covering this subject. First-line therapy: Studies from the 70ies could demonstrate that doxorubicin was as effective as alkylating agents. The combination of anthracylines and alkylating agents provided superior results compared with alkylating agents alone. Further improvements were gained by the introduction of platinum-anthracyline combination regimens. Doxorubicin and epirubicin showed comparable activity when combined with platinum. The comparison between platinum-anthracyline containing combination regimens with platinum based regimens without anthracylines did not provide definitive answers. The majority of studies (with relatively small patient numbers) did not reveal any significant benefit for the anthracyline containing regimens. In contrast, four meta-analyses combining several studies showed a significant improvement when anthracylines were added to platinum based regimens. This question came up again when standard treatment for ovarian cancer was modified by the introduction of paclitaxel in the mid 90ies. Currently, two randomized large intergroup trials evaluate the role of anthracyclines in combination with platinum and paclitaxel. Results from these studies will be available in 1-2 years and might help to describe the role for anthracyclines in ovarian cancer treatment more precisely. Until then, the use of anthracyclines in upfront chemotherapy of ovarian cancer outside of clinical trials cannot be recommended. 2n-line therapy: The anthracyclines doxorubicin and epirubicin are among the most active single agents for the treatment of platinum refractory ovarian cancer. Both agents achieved tumor responses in up to 25%. Preliminary data suggest, that the combination with paclitaxel could increase efficacy. No such effect was reported for any other combination. In contrast, single agent anthracyclines cannot be recommended for treatment of platinum sensitive tumors. However, combining anthracyclines with platinum resulted in remarkable response rates of more than 50% of patients with platinum sensitive tumors. Only few studies report the use of anthracylines after platinum and paclitaxel containing first-line chemotherapy. Preliminary data from small studies (40 patients) suggest that anthracyclines showed activity in this particular population. No final conclusions can be drawn. There is a need for developing effective 2nd-line therapies for patients failing platinum and paclitaxel combination regimens. Among others, anthracyclines should be evaluated in this clinical setting.

Antibiotics, Antineoplastic↗

PubMed1999

[Secondary debulking after dose-intensified chemotherapy of ovarian carcinoma].

Only 20-40% of patients with advanced ovarian cancer have no residual disease after primary cytoreductive surgery. For patients with residual tumor and good response to chemotherapy new therapeutic procedures have to be discussed. In our study the role of secondary debulking surgery, especially after G-CSF supplied dose intensification was evaluated. Between January 1986 and December 1995, 506 patients with primary ovarian cancer were treated at our institution. 117 patients with residual tumor after primary surgery had secondary debulking after four to six cycles of platinum based chemotherapy, 26 of them had G-CSF supplemented dose intensification by shortened therapy intervals. After secondary debulking 43% had no residual disease, 37% had residual tumor less than 2 cm and 20% more than 2 cm. Mean survival in patients without residual disease was 47 months and significantly longer than in patients without secondary debulking with only 35 months. In 25 to 26 patients with dose intensification chemotherapy cycles could be applied regularly, the results were in the expected range. Secondary debulking surgery can prolong survival in those patients without residual tumor after secondary surgery. Dose intensification is possible without remarkable side effects. In our study the percentage of patients without residual tumor could not be increased by dose intensification.

Adult↗

PubMed1999

First-line chemotherapy with epirubicin, paclitaxel, and carboplatin for advanced ovarian cancer: a phase I/II study of the Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group.

PURPOSE: Despite the progress that has been achieved over the years, survival rates in patients with advanced ovarian cancer are still disappointing. New methods to improve the efficiency of first-line chemotherapy are warranted. One method to improve results is to add more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines are among the candidates for incorporation as the "third drug" into first-line regimens for advanced ovarian cancer. PATIENTS AND METHODS: We performed a phase I/II trial with escalating doses of epirubicin (60, 75, and 90 mg/m2) combined with fixed doses of paclitaxel and carboplatin in 27 previously untreated patients with advanced gynecologic malignancies. RESULTS: Dose-limiting toxicity occurred at dose level 2 (75 mg/m2 epirubicin) and consisted of myelosuppression (neutropenia, thrombocytopenia). No dose-limiting, nonhematologic toxicities were observed. The maximum tolerable dose was epirubicin 60 mg/m2 (E) combined with a 3-hour infusion of paclitaxel 175 mg/m2 (T) and carboplatin AUC 5 (Carbo). Preliminary analysis indicated promising activity against ovarian cancer. CONCLUSION: The three-drug combination ET-Carbo, given according to the outlined dose and schedule, should be considered for further phase III evaluation. A randomized German-French intergroup trial comparing ET-Carbo with carboplatin-paclitaxel has already been initiated.

Adult↗

PubMed1999

Low affinity binding of an LFA-3/IgG1 fusion protein to CD2+ T cells is independent of cell activation.

Quantitative analysis of binding of the bivalent recombinant soluble fusion protein, LFA-3/IgG1, shows that the fusion protein binds to human CD2+ PBLs primarily through low affinity (KD approximately 140 microM) but also through high avidity (90 nM) interactions. The concentration dependence for LFA-3/IgG1 PBL binding took the form of two overlapping bell-shaped curves separated by a clear and reproducible minimum. This was accounted for in part by minor heterogeneity in the LFA-3/IgG1 preparations, and potentially by the ability of the ligand to bind to both CD2 and Fc receptors (FcR), best evidenced by the distinct binding properties of the fusion protein to NK and T cells. The low affinity LFA-3/ IgG1 binding to T cells is consistent with binding to CD2 only, and is in agreement with the low affinity reported for interactions between soluble forms of LFA-3 and CD2 by surface plasmon resonance technology. Moreover, as the low affinity determinations are similar for CD2 on resting and activated T cells, although the CD2 molecule has been reported to be altered to reveal new epitopes upon T cell activation, the binding data argue against multiple cell activation-dependent affinity states of CD2 for LFA-3 binding. This is distinct from that observed with other adhesion partners, and suggests that the different adhesion pathways utilize distinct mechanisms to mediate cell adhesion.

Animals↗

PubMed1998

Susceptibility of alpine ibex to conjunctivitis caused by inoculation of a sheep-strain of Mycoplasma conjunctivae.

We evaluated the susceptibility of alpine ibex (Capra ibex ibex) to mycoplasmal conjunctivitis induced by a strain of Mycoplasma conjunctivae isolated from domestic sheep by inoculation of three alpine ibexes with 1.2 x 10(6) colony forming units of M. conjunctivae in the conjunctival sac of both eyes. One more ibex was exposed to the infection by contact. Experimental animals were free of M. conjunctivae and ocular Chlamydia infection before inoculation. Conjunctivitis and serous to mucous lachrymation became apparent in all four ibexes. Clinical signs began within 2 days in inoculated animals and 22 days after the beginning of the experiment in the contact ibex. M. conjunctivae was demonstrated up to the 63th day post-inoculation by cultural and PCR-methods. After 63 days, histopathologic examination revealed nearly normal ocular tissues, and M. conjunctivae could be detected from two eyes only. No other infectious agents which might cause conjunctivitis or keratitis, including Chlamydia psittaci and Branhamella ovis, were involved. Our investigation indicates that sheep-strains of M. conjunctivae can induce conjunctivitis in alpine ibex, thus showing pathogenicity of this organism for Caprinae species other than domestic sheep and goats.

Animals↗

PubMed1998

Treosulfan as an effective second-line therapy in ovarian cancer.

Despite radical surgery and aggressive platinum-containing primary chemotherapy, the outcome of patients with advanced ovarian cancer remains extremely poor; most of them suffer from recurrent or progressive disease. These patients should be treated with an effective second-line therapy showing only few toxic side effects so as not to affect quality of life. From July 1992 to August 1996, 88 patients with recurrent or progressive ovarian cancer have been treated with treosulfan, an alkylating agent, in our department. All of them could be evaluated for toxicity and 80 for response. There were 2 complete and 13 partial responses, giving an objective response rate of 19%. Among responding patients, median survival time was 41 months. Thirty-four percent of the patients had stable disease with median survival of 18 months. Thirty-eight (47%) nonresponding patients showed a survival time of only 5 months. In 48 women with progressive disease within 12 months after primary therapy, a response rate of 19% and stable disease in 31% could be achieved. Toxic side effects were rare and moderate in intensity. Life-threatening myelosuppression, emesis resistant to therapy, and alopecia were not observed. It can be concluded that tresosulfan is an effective drug in second-line therapy for patients with recurrent or progressive ovarian cancer without affecting quality of life.

Adult↗

PubMed1998

Primary culture of dispersed skin epidermal cells of rainbow trout Oncorhynchus mykiss Walbaum.

This is the first report on a primary culture of dispersed skin epidermal cells of rainbow trout Oncorhynchus mykiss Walbaum. These primary cells revealed a low seeding efficiency after 3 days (11.6 +/- 4.6%), whereas subcultured cells had a higher seeding efficiency at the same time point (75.5 +/- 34.0%) and increased in cell number (150-200% of seeded cells after 20 to 30 days). The cells were characterized applying histological, immunocytochemical and ultrastructural methods. The culture consisted of undifferentiated keratinocytes. Mucous cells as well as differentiated epithelial cells were absent. To date the cells were cultured for maximally 9 passages and 402 days and therefore provide the possibility for long-term studies.

Animals↗

PubMed1998

Heat shock protein (hsp70) in brown trout epidermis after sudden temperature rise.

So far, hsp70 has not yet been studied in the fish skin. This organ has a potential as an indicator organ and we investigate whether hsp70 could be used as a biomarker. In this study, we examined whether and how the epidermis reacts to a temperature rise. Brown trout, Salmo trutta fario, were exposed to higher temperature for 2 h and were allowed to recover subsequently. Samples were taken from controls, after heat shock, as well as after 24 and 48 h of recovery. The occurrence of hsp70 in trout skin was examined by Western blot. The amount of hsp70 was higher after 2-h heat shock and was rising until the end of the experiment. Immunocytochemically, hsp70 was detected in epidermal filament cells. After 2-h heat shock, hsp70 was predominantly located in the nucleus. At this time, light and electron microscopy revealed several features known to occur under a variety of stressors. Ultrastructurally, the appearance of compact filament aggregates in pavement cells was remarkable. After 24 h of recovery, filament compaction was lacking and after 48 h aspects of regeneration were obvious. However, an increased amount of apoptotic cells in the epidermis was prominent at this time only.

Animals↗

PubMed1998

Immunohistochemical detection of vitellogenin in male brown trout from Swiss rivers.

The detection of vitellogenin, a yolk precursor protein, may serve as a biomarker for exposure to environmental oestrogens as its induction by xenobiotic oestrogens in the immature and male fish has been reported repeatedly. In the present work, juvenile brown trout were injected with oestradiol (5 microg g(-1) body weight oestradiol benzoate) in order to assess the induction and organ distribution of vitellogenin by means of immunohistochemistry. In addition, brown trout collected from Swiss rivers were analysed. Vitellogenin was detected in the oestradiol-injected juvenile trout but not in uninjected controls. The presence of vitellogenin was also demonstrated in a male and an immature feral brown trout from one of two locations downstream of three sewage treatment plants. In contrast, no positive staining was found in livers of trout upstream of the respective plants. The results demonstrate the suitability of immunohistochemistry for monitoring feral fish for the presence of vitellogenin production.

Animals↗

PubMed1998

Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta).

PURPOSE: Two recombinant IFN-beta products have been approved for the treatment of multiple sclerosis, a glycosylated form with the predicted natural amino acid sequence (IFN-beta-1a) and a non-glycosylated form that has a Met-1 deletion and a Cys-17 to Ser mutation (IFN-beta-1b). The structural basis for activity differences between IFN-beta-1a and IFN-beta-1b, is determined. METHODS: In vitro antiviral, antiproliferative and immunomodulatory assays were used to directly compare the two IFN-beta products. Size exclusion chromatography (SEC), SDS-PAGE, thermal denaturation, and X-ray crystallography were used to examine structural differences. RESULTS: IFN-beta-1a was 10 times more active than IFN-beta-1b with specific activities in a standard antiviral assay of 20 x 10(7) IU/mg for IFN-beta-1a and 2 x 10(7) IU/mg for IFN-beta-1b. Of the known structural differences between IFN-beta-1a and IFN-beta-1b, only glycosylation affected in vitro activity. Deglycosylation of IFN-beta-1a produced a decrease in total activity that was primarily caused by the formation of an insoluble disulfide-linked IFN precipitate. Deglycosylation also resulted in an increased sensitivity to thermal denaturation. SEC data for IFN-beta-1b revealed large, soluble aggregates that had reduced antiviral activity (approximated at 0.7 x 10(7) IU/mg). Crystallographic data for IFN-beta-1a revealed that the glycan formed H-bonds with the peptide backbone and shielded an uncharged surface from solvent exposure. CONCLUSIONS: Together these results suggest that the greater biological activity of IFN-beta-1a is due to a stabilizing effect of the carbohydrate on structure.

Adjuvants, Immunologic↗

PubMed1998

Transient increase in chloride cell number and heat shock protein expression (hsp70) in brown trout (Salmo trutta fario) exposed to sudden temperature elevation.

The native cold-adapted brown trout (Salmo trutta fario) is often the subject of biomonitoring field studies. Groups of trout were exposed to a sudden temperature rise, from 8 degrees C to 19 degrees C for two hours, and thereafter set back to 8 degrees C. Gill samples of control animals, of fish after the exposure period, and after 24 and 48 hours of recovery at a temperature of 8 degrees C were examined histologically, immunohistochemically, electron microscopically, and by Western blot analysis. By means of immunohistochemistry and electron microscopy, an increase of chloride cells was observed after the temperature elevation. During the recovery period the number of chloride cells decreased. Western blot analysis for stress proteins (hsp70), widely used as a biomarker for environmental stress, was performed from skin and gill. Whereas in the gill both isoforms, the constitutive and the heat inducible form, of hsp70 were detected in all groups, in the skin the control animals only showed the constitutive form. After two hours of exposure both isoforms were visible. An increased expression of hsp70 could be demonstrated in both organs after the exposure. Comparison of the hsp70 values between gill and skin showed tissue-specific differences during the recovery period. In the gill hsp70 rapidly decreased, while in the skin the level remained elevated over the whole observation period. When hsp70 is used as a biomarker in field studies, the fast and organ-specific reaction in the gill and skin of brown trout has to be taken into consideration.

Animals↗

PubMed1998

[Occurrence of white liver dis in lambs in Switzerland].

The white liver disease was first observed in the canton of Berne in 1985. Until 1995 we could observe the outbreak of the disease in seven flocks. The first clinical signs were anorexia, then delayed growth, weight loss and finally cachexy. The animals showed photosensitivity on ears, eyelids and nose. A hematological and blood biochemical examination revealed a mild normochrome, normocytic anemia as well as a significant elevation of GGT and a mild elevation of AST values. By examining the swollen grey-white to yellow livers histologically we could find a mostly pronounced, primarily panacinar, degenerative fatty degeneration of the liver, ceroid pigment in the macrophages, biliary hyperplasia as well as a secondary periportal hepatitis.

Animals↗

PubMed1997

Low affinity interaction of human or rat T cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity.

The mechanism by which low affinity adhesion molecules function to produce stable cell-cell adhesion is unknown. In solution, the interaction of human CD2 with its ligand CD58 is of low affinity (500 mM-1) and the interaction of rat CD2 with its ligand CD48 is of still lower affinity (40 mM-1). At the molecular level, however, the two systems are likely to be topologically identical. Fluorescently labeled glycosylphosphatidylinositol-anchored CD48 and CD58 were prepared and incorporated into supported phospholipid bilayers, in which the ligands were capable of free lateral diffusion. Quantitative fluorescence imaging was used to study the binding of cell surface human and rat CD2 molecules to the fluorescent ligands in contact areas between Jurkat cells and the bilayers. These studies provide two major conclusions. First, CD2/ligand interactions cooperate to align membranes with nanometer precision leading to a physiologically effective two-dimensional affinity. This process does not require the intact cytoplasmic tail of CD2. Second, the degree of membrane alignment that can be achieved by topologically similar receptors deteriorates with decreasing affinity. This suggests an affinity limit for the ability of this mode of cooperativity to achieve stable cell-cell adhesion at approximately 10 mM-1.

Animals↗

PubMed1997

The crystal structure of human interferon beta at 2.2-A resolution.

Type I interferons (IFNs) are helical cytokines that have diverse biological activities despite the fact that they appear to interact with the same receptor system. To achieve a better understanding of the structural basis for the different activities of alpha and beta IFNs, we have determined the crystal structure of glycosylated human IFN-beta at 2.2-A resolution by molecular replacement. The molecule adopts a fold similar to that of the previously determined structures of murine IFN-beta and human IFN-alpha2b but displays several distinct structural features. Like human IFN-alpha2b, human IFN-beta contains a zinc-binding site at the interface of the two molecules in the asymmetric unit, raising the question of functional relevance for IFN-beta dimers. However, unlike the human IFN-alpha2b dimer, in which homologous surfaces form the interface, human IFN-beta dimerizes with contact surfaces from opposite sides of the molecule. The relevance of the structure to the effects of point mutations in IFN-beta at specific exposed residues is discussed. A potential role of ligand-ligand interactions in the conformational assembly of IFN receptor components is discussed.

Computer Simulation↗