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Biomedical subjects

M Kaufmann

Publications and source records attributed to M Kaufmann.

At least 109 records · Page 6Linked to original sources
PubMed2000

Polo-like kinase: a novel marker of proliferation: correlation with estrogen-receptor expression in human breast cancer.

Previous data have shown that the mRNA-expression of the serin/threonine-kinase polo-like kinase (PLK) is closely correlated with the survival of patients suffering from a subset of malignant tumors. PLK-mRNA and protein-expression are restricted to cells in the cell cycle. PLK-mRNA-transcripts are highly abundant in proliferating cells; no gene expression is found in G0-phase cells. Here we investigated the mRNA- and protein-expression of PLK- and estrogen-receptor (ER) in human breast-carcinoma by northern-blotting, RT-PCR and immunohistochemistry. The expression of MIB-I was determined on serial sections. Analysis of the immunohistochemical data revealed a close correlation between the ER and PLK-expression (r = 0.677; p = 0.001, n = 30). No relationship between the mRNA-expression of ER and PLK was found. Furthermore, no correlation for the protein expression of PLK and MIB-I exists. The influence of estrogen (ES) is known to have proliferative potential. The expression of ER correlates with the ES-plasma-level. In addition, the hormone cycle of premenopausal women undergoes rapid vacillations with varying effects on the proliferating tumor cells, e.g., growth induction. Our results therefore show that ER-expression is not only of therapeutic value for the clinician, but it may also be a tool for determining the tumor proliferation index more precisely by integrating the hormone-mediated proliferation stimulus.

Adult↗
PubMed2000

Exemestane improves survival compared with megoestrol acetate in postmenopausal patients with advanced breast cancer who have failed on tamoxifen. results Of a double-blind randomised phase III trial.

Exemestane is an aromatase inactivator. 769 Postmenopausal women with advanced breast cancer who had failed on tamoxifen were randomised to exemestane or megoestrol acetate in this double-blind trial. Objective response rate was similar between treatments. Median time to progression, time to treatment failure and overall survival was significantly longer with exemestane. Drug-related withdrawals and drug-related deaths were more common with megoestrol acetate.

Androstadienes↗
PubMed2000

Cell cycle-related expression and ligand binding of peripheral benzodiazepine receptor in human breast cancer cell lines.

The aim of this study was to measure the expression of peripheral benzodiazepine receptors (PBR) as well as mitochondria content in different phases of the cell cycle of BT-20 and MCF-7 breast cancer cell lines, using two-parameter flow cytometric analyses. The PBR expression as well as mitochondria mass, were found to increase as cells pass through different stages of the cell cycle, whereas the amount of PBR in quiescent cells was very low. Binding capacity for the PBR ligand [3H]-Ro5-4864 was strongly related to the phase of the cell cycle with a positive correlation (r=0.98) with a high percentage of cells in S phase. Incubation of BT-20 cells in serum-deprived medium with nanomolar concentrations of Ro5-4864 caused an increase in S phase cells. This effect was not observed in MCF-7 cells. Using micromolar concentrations of Ro5-4864, both BT-20 and MCF-7 cells were reversibly arrested in the G(0/1) phase.

Breast Neoplasms↗
PubMed2000

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification.

Although the neoplastic significance of the chromosome changes widespread in Hodgkin's disease (HD) remains obscure, a distinct cytogenetic picture has emerged combining aneuploidy with structural rearrangements clustered at certain breakpoints. Notably absent are the recurrent chromosome translocations which distinguish other hematopoietic neoplasms and serve as clues to underlying oncogene alterations. The paucity of neoplastic cells in HD biopsies hinders detailed chromosome analysis. As an alternative, we investigated a panel of well characterized cell lines by classical and molecular cytogenetics, using single-gene and subtelomeric probes, including three autologous HD examples (HDLM-1/2/3) analyzed by 'spectral karyotyping' - the first complete HD karyotype to be documented. Although complex, most rearrangements in HDLM cells arose in vivo and included few rare but many typical HD breakpoints, notably at the r(ibosomal)DNA regions. Two types of genomic rearrangement involving DNA repeats were conspicuous: insertion and genomic amplification/coamplification of rDNA-the first genomic rDNA rearrangements to be reported in a tumor cell, and the first example of multiple 'jumping translocations' (JT). Of four subtelomeric microsatellite repeats tested in HDLM cells, three exhibited interstitial sites at JT, of which two (at 5qter and 9pter) were respectively associated with deletion of the 5q31-32 myeloid region, and coamplification of a recently described HD-recurrent amplicon at 9p2 together with transcriptionally silent rDNA. Altogether, three out of four HD cell lines carried interstitial 9p subtelomeres and rDNA rearrangements. Taken together, these data suggest tumorigenic rearrangements may be facilitated by 'hitchhiking' along with mobile DNA repeat sequences which may target gene rearrangement at 9p in HD. Southern analysis of parallel rearrangements within rDNA intergenic spacers in HDLM cells highlighted several at, or near, retroposons. As well as validating HD cell lines as cytogenetic models, and resources for identifying genes rearranged in HD, our findings warrant further investigation of the roles of DNA repeat sequences, notably subtelomeric microsatellites, rDNA spacer sequences and retroposons as facilitators and markers of tumor-gene rearrangement.

Base Sequence↗
PubMed2000

VRE in the Republic of Ireland: clinical significance, characteristics and molecular similarity of isolates.

There have been increasing reports worldwide of vancomycin resistant enterococci (VRE) since they were first noted over ten years ago. This study sought to investigate the clinical significance of VRE in Ireland and to compare the phenotypic, genotypic and molecular characteristics of isolates recovered from patients in different institutions. The relative contribution of inter-hospital transmission of strains to the dissemination of VRE in Ireland was assessed. Hospital surveillance for VRE is not well established in Ireland. The organism has been detected in seven hospitals. Detection has been predominantly in oncology inpatients in large tertiary referral hospitals in the Dublin metropolitan area in whom strains generally represent asymptomatic gastrointestinal tract colonization. The predominant species is E. faecium with the Van A resistance phenotype. Twenty-seven (87) of 31 isolates from one unit were shown to be of the same or closely related strain as were 10 (63%) of 16 from another unit, indicating significant nosocomial transmission within institutions. There was no evidence for inter-hospital transmission of VRE. VRE is established in Ireland and nosocomial transmission readily occurs. Regular surveillance for VRE is indicated in high-risk populations in large institutions, specific risk factors for the acquisition of VRE need to be defined and optimal control and preventative strategies need to he instituted to detect and preempt the spread of this organism.

Adolescent↗
PubMed2000

Prospective evaluation of 3 risk stratification scores in cardiac surgery.

BACKGROUND: The aim of the study was to evaluate 3 different risk stratification scores in cardiac surgery, based on the hospital results of 1,299 patients. METHODS: From June 1995 to December 1997, all patients (n = 1,299) undergoing coronary artery bypass grafting (CABG) and/or heart valve surgery were prospectively enrolled. The postoperative in-hospital outcome (mortality, morbidity and length of hospital stay) was analysed in relation to three different risk stratification scores (Parsonnet, Higgins and French score). RESULTS: The results of 1,299 patients (mean age 62.8 +/- 10.2 years) were analysed. 10 patients died, accounting for a total mortality of 0.8%. 13 patients (1%) underwent cardiopulmonary resuscitation. In 25 patients (1.9%), perioperative myocardial infarction occurred. Performance of the 3 systems was assessed by evaluating discrimination with receiver operating characteristic (ROC) curves. The area under the ROC curve was 0.761 for Parsonnet, 0.786 for Higgins and 0.798 for French score. The French and the Higgins score showed an increase of in-hospital mortality, morbidity and length of stay in relation to increasing risk classes. CONCLUSION: For objective evaluation of the outcome in cardiac surgery, case-mix severity needs to be considered, which is reflected by preoperative risk stratification scores. In our study, all the 3 scores showed a high discrimination and are appropriate tools to assess mortality in cardiac surgery. Especially the French and the Higgins score (restricted to 5 groups), due to their simplicity, were useful to predict postoperative outcome in clinical routine.

Adolescent↗
PubMed2000

Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group.

PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

Administration, Oral↗
PubMed2000

Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study.

We compared the efficacy and safety of the oral aromatase inactivator exemestane (EXE) with megestrol acetate (MA) in women with metastatic breast cancer. This phase III randomized, double-blind, multicenter study was conducted in 769 postmenopausal women who had experienced tamoxifen failure. Treatment arms consisted of EXE 25 mg once daily (n=366) or MA 40 mg four times daily (160 mg daily; n=403). Peer-reviewed, intent-to-treat analyses demonstrated that EXE induced a trend toward higher rates of complete response (CR)+partial response (PR) (15.0% vs. 12.4%) and of CR+PR+stable disease (SD)=24 weeks (37.4% vs. 34.6%), but differences were not statistically significant. Statistically significant differences favoring EXE were seen in median duration of CR+PR+SD=24 weeks (60.1 vs. 49.1 weeks; P=0.025), time to tumor progression (20.3 vs. 16.6 weeks; P=0.037), time to treatment failure (16.3 vs. 15.7 weeks; P=0.042), and overall survival (not reached vs. 123.4 weeks; P=0.039). Both treatments were well tolerated, but MA was associated with more grade 3 or 4 weight gain (8% vs. 17%, P=0.001); the pain score was sim-ilar in both groups. There was a trend toward superiority in treatment-related signs and symptoms (TRSS) with EXE. There was greater improvement in the pain score and TRSS in patients achieving an objective response with EXE vs. MA. Quality of life improved or was similar for EXE in most domains. Exemestane offers an important new treatment option for postmenopausal women with hormone-responsive breast cancer.

Administration, Oral↗
PubMed2000

Cervical intraepithelial neoplasia in human immunodeficiency virus-positive patients.

Cervical intraepithelial neoplasia (CIN) is common in patients positive for human immunodeficiency virus (HIV). The questions are whether the management of CIN in these patients should be different from that of HIV-negative women, whether there are any prognostic factors to indicate the course of CIN, and whether the latter is influenced by antiretroviral therapy. A total of 267 HIV-seropositive women were counseled and examined in our colposcopic clinic. Of that number, 53 patients died during the observation period; 74% of these patients were immunosuppressed (CD4 count < 200 cells/mm3), and 45% were given diagnoses of CIN. The incidence of CIN was significantly higher in patients with CD4 less than 200 cells/mm3. Neither the route of HIV infection nor the HPV status nor smoking habits correlated with CIN. CIN relapse was histologically confirmed in 28% of patients who underwent complete surgical removal. Immune status plays an important role in HIV-positive women not only with respect to survival but with respect to CIN.

Adult↗
PubMed2000

Predictive value of serum interleukin-6 and -8 levels in preterm labor or rupture of the membranes.

BACKGROUND: The aim of this prospective study was to examine if serum concentrations of cytokines are of value in the identification of patients at risk for preterm delivery. METHODS: Interleukin- 1beta,2,4,6,8 and tumor necrosis factor alpha were determined between 25 and 37 weeks of gestation in the serum of 72 consecutive patients with preterm labor, 38 patients with preterm rupture of the membranes, and 24 healthy pregnant women as a control group. Material was collected within 18 hours after hospitalization and was immediately centrifuged and shock frozen. RESULTS: Significantly increased serum levels were found for interleukin-6 and -8 in patients with preterm labor or preterm rupture of the membranes when compared to the control group (p<0.001 and p<0.005, respectively). In patients with preterm rupture of the membranes and interleukin-6 levels above the median of 4.0 pg/ml the delivery occurred significantly earlier than in patients with lower levels (1 versus 5.5 days; p=0.005). Patients of both pathology groups with detectable (>18 pg/ml). Interleukin-8 levels had a shorter pregnancy duration when compared to other patients (p=0.05 for preterm labor and p=0.04 for preterm rupture of the membranes). Interleukin-1beta,2,4, and tumor necrosis factor alpha were not correlated with clinical outcome. CONCLUSIONS: Increased serum interleukin-6 and -8 levels are associated with a shorter interval between onset of preterm rupture of the membranes and delivery and should therefore be further evaluated for their use in clinical practice.

Adult↗
PubMed1999

Widespread intraspecies cross-contamination of human tumor cell lines arising at source.

We present a panoptic survey of cell line cross-contamination (CLCC) among original stocks of human cell lines, investigated using molecular genetic methods. The survey comprised 252 consecutive human cell lines, almost exclusively tumor-derived, submitted by their originators to the DSMZ and 5 additional cell repositories (CRs), using a combination of DNA profiling (4-locus minisatellite and multilocus microsatellite probes) and molecular cytogenetics, exploiting an interactive database (http://www.dsmz.de/). Widespread high levels of cross-contaminants (CCs) were uncovered, affecting 45 cell lines (18%) supplied by 27 of 93 originators (29%). Unlike previous reports, most CCs (42/45) occurred intraspecies, a discrepancy attributable to improved detection of the more insidious intraspecies CCs afforded by molecular methods. The most prolific CCs were classic tumor cell lines, the numbers of CCs they caused being as follows: HeLa (n = 11), T-24 (n = 4), SK-HEP-1 (n = 4), U-937 (n = 4) and HT-29 (n = 3). All 5 supposed instances of spontaneous immortalization of normal cells were spurious, due to CLCC, including ECV304, the most cited human endothelial cell line. Although high, our figure for CCs at the source sets a lower limit only as (i) many older tumor cell lines were unavailable for comparison and (ii) circulating cell lines are often obtained indirectly, rather than via originators or CRs. The misidentified cell lines reported here have already been unwittingly used in several hundreds of potentially misleading reports, including use as inappropriate tumor models and subclones masquerading as independent replicates. We believe these findings indicate a grave and chronic problem demanding radical measures, to include extra controls over cell line authentication, provenance and availability.

Cell Culture Techniques↗
PubMed1999

Cross-reactive staining of normal bone-marrow cells by monoclonal antibody 2E11.

The monoclonal antibody (MAb) 2E11 is commonly used for detection of microdisseminated epithelial cells in bone marrow of cancer patients. Surprisingly, in an earlier report 2E11 was shown to bind to mononuclear cells in bone marrow in 61% of healthy donors. In the present study we tested whether this cross-reaction with non-epithelial bone-marrow cells can be characterized further. In addition, we analyzed the influence of 2E11 concentration on the staining of mononuclear cells. We performed immunocytochemical double stainings of bone-marrow aspirations from breast-cancer patients using 2E11/A45-B/B3 (MAb against cytokeratin 8, 18, 19) and 2E11/CD45 (MAb against CD45-leukocyte common antigen), while tumor cell lines MCF-7 and K526 as well as bone marrow from breast-cancer patients were treated with different concentrations of 2E11. A portion of 2E11-positive cells was characterized as hematopoietic cells by CD-45-binding, while others were identified as epithelial cells by A45-B/B3-binding. We defined a concentration of 2E11 to immunolabel epithelial cells and distinguish hematopoietic cells. Higher concentrations of 2E11 enhance staining of hematopoietic cells, to match that of epithelial cells. We conclude that 2E11 shows cross-reactivity to epitopes displayed by hematopoietic cells. However, specific staining of epithelial cells can be achieved. As long as there is no antibody available which is highly specific for epithelial cells, detection of microdisseminated tumor cells in bone marrow by antigen-antibody reaction should be verified morphological criteria.

Antibodies, Monoclonal↗
PubMed1999

[The value of music in postoperative care].

During the immediate postoperative period good monitoring, adequate analgesia and competent, comprehensive care are of paramount importance. The effect of music in the recovery room raised my interest as an additional "instrumentarium". It is my intent to motivate to take advantage of the many-fold uses of music in the postoperative phase.

Anesthesia Recovery Period↗
PubMed1999

Molecular cloning and functional expression of two members of mouse NeuAcalpha2,3Galbeta1,3GalNAc GalNAcalpha2,6-sialyltransferase family, ST6GalNAc III and IV.

Two cDNA clones encoding NeuAcalpha2,3Galbeta1,3GalNAc GalNAcalpha2, 6-sialyltransferase have been isolated from mouse brain cDNA libraries. One of the cDNA clones is a homologue of previously reported rat ST6GalNAc III according to the amino acid sequence identity (94.4%) and the substrate specificity of the expressed recombinant enzyme, while the other cDNA clone includes an open reading frame coding for 302 amino acids. The deduced amino acid sequence is not identical to those of other cloned mouse sialyltransferases, although it shows the highest sequence similarity with mouse ST6GalNAc III (43.0%). The expressed soluble recombinant enzyme exhibited activity toward NeuAcalpha2, 3Galbeta1, 3GalNAc, fetuin, and GM1b, while no significant activity was detected toward Galbeta1,3GalNAc or asialofetuin, or the other glycoprotein substrates tested. The sialidase sensitivity of the 14C-sialylated residue of fetuin, which was sialylated by this enzyme with CMP-[14C]NeuAc, was the same as that of ST6GalNAc III. These results indicate that the expressed enzyme is a new type of GalNAcalpha2,6-sialyltransferase, which requires sialic acid residues linked to Galbeta1,3GalNAc residues for its activity; therefore, we designated it mouse ST6GalNAc IV. Although the substrate specificity of this enzyme is similar to that of ST6GalNAc III, ST6GalNAc IV prefers O-glycans to glycolipids. Glycolipids, however, are better substrates for ST6GalNAc III.

Amino Acid Sequence↗
PubMed1999

Cytokine release from placental endothelial cells, a process associated with preterm labour in the absence of intrauterine infection.

There is currently a great deal of interest in the role that cytokines may play in the processes mediating preterm as well as normal term labour. In case of preterm delivery a cause-effect relationship between infection, uncontrollable preterm labour, and increased uterine cytokine concentrations is widely accepted, but there is considerable information that increased uterine cytokine release is also a condition in normal term labour and preterm labour not due to infection. Thereby, the exact cellular sources of cytokine production have not yet been identified. In the present study, the authors used immunohistochemical analysis to localize interleukin 1beta (IL-1beta) interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) immunoreactivity within trophoblastic villi and fetal membranes. In the absence of chorioamnionitis, uncontrollable preterm labour, and also normal term labour was associated with strong immunoreactivity for IL-1beta and IL-6 in the endothelial cells within trophoblastic villi. In contrast, preterm delivery accompanied by histologically confirmed chorioamnionitis, was not associated with increased expression of cytokine antigens within endothelial cells of the fetal vascular system, but strong cytokine activity was found in polymorphonuclear cells infiltrating the amniochorionic membranes. Therefore, the data suggest two well-defined subgroups among patients delivering preterm. Thereby, increased uterine cytokine concentrations may be realized in both groups, but the cellular sources of cytokine production may be different.

Adult↗
PubMed1999

Lamellar body counts in amniotic fluid for prediction of fetal lung maturity.

OBJECTIVE: Comparison of three different methods of fetal lung maturity (FLM) testing in amniotic fluid (AF) to predict fetal respiratory distress syndrome (RDS): phospholipid concentration, phosphatidylglycerol (PG) and lamellar body count (LBC). STUDY DESIGN: 315 amniotic fluid (AF) samples were tested, 291 by determination of phospholipid, 237 by PG and 68 by LBC. Eighty one patients (26%) delivered within 3 days, incidence of RDS was 7% (n = 6). Correlation of phospholipids and LBC to gestational age was analyzed as well as correlation of LBC and PG versus phospholipid concentration. Sensitivity and specificity for all three methods were calculated. RESULTS: Phospholipids and LBC increased exponentially with gestational age (rregr = 0.54, p < 0.01, rregr = 0.76, p < 0.01) showing a curvilinear function. There was a linear correlation between both methods (rcorr = 0.51, p < 0.01, n = 47). Sensitivity for prediction of RDS was 80% for phospholipids compared to 83% for LBC and 67% for PG. Specificity was best for PG (92%) followed by phospholipids (85%). While positive predictive value was low (27% for phospholipids and 50% for LBC), negative predictive value varied between 97% and 100%. CONCLUSIONS: LBC is a simple and reliable method for FLM testing, with a sensitivity comparable to phospholipid testing and a somewhat lower specificity (67% vs. 85%). It may be useful for screening of FLM in a cascade approach.

Amniotic Fluid↗
PubMed1999

Specific binding of benzodiazepines to human breast cancer cell lines.

Binding of [3H]Ro5-4864, a peripheral benzodiazepine receptor (PBR) agonist, to BT-20 human, estrogen- (ER) and progesterone- (PR) receptor negative breast cancer cells was characterized. It was found to be specific, dose-dependent and saturable with a single population of binding sites. Dissociation constant (K(D)) was 8.5 nM, maximal binding capacity (Bmax) 339 fM/10(6) cells. Ro5-4864 (IC50 17.3 nM) and PK 11195 (IC50 12.3 nM) were able to compete with [3H]Ro5-4864 for binding, indicating specificity of interaction with PBR. Diazepam was able to displace [3H]Ro5-4864 from binding only at high concentrations (>1 microM), while ODN did not compete for PBR binding. Thymidine-uptake assay showed a biphasic response of cell proliferation. While low concentrations (100 nM) of Ro5-4864, PK 11195 and diazepam increased cell growth by 10 to 20%, higher concentrations (10-100 microM) significantly inhibited cell proliferation. PK 11195, a potent PBR ligand, was able to attenuate growth of BT-20 cells stimulated by 100 nM Ro5-4864 and to reverse growth reduction caused by 1 and 10 microM Ro5-4864, but not by 50 microM and 100 microM. This indicates that the antimitotic activity of higher concentrations of Ro5-4864 is independent of PBR binding. It is suggested, that PBR are involved in growth regulation of certain human breast cancer cell lines, possibly by supplying proliferating cells with energy, as their endogenous ligand is a polypeptide transporting Acyl-CoA.

Benzodiazepinones↗