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Biomedical subjects

W Zschiesche

Publications and source records attributed to W Zschiesche.

At least 19 recordsLinked to original sources
PubMed2006

Asbestos Surveillance Program Aachen (ASPA): initial results from baseline screening for lung cancer in asbestos-exposed high-risk individuals using low-dose multidetector-row CT.

The purpose of this study was to assess the prevalence of lung cancer in a high-risk asbestos-exposed cohort using low-dose MDCT. Of a population of 5,389 former power-plant workers, 316 were characterized as individuals at highest risk for lung cancer according to a lung-cancer risk model including age, asbestos exposure and smoking habits. Of these 316, 187 (mean age: 66.6 years) individuals were included in a prospective trial. Mean asbestos exposure time was 29.65 years and 89% were smokers. Screening was performed on a 16-slice MDCT (Siemens) with low-dose technique (10/20 mAs(eff.); 1 mm/0.5 mm increment). In addition to soft copy PACS reading analysis on a workstation with a dedicated lung analysis software (LungCARE; Siemens) was performed. One strongly suspicious mass and eight cases of histologically proven lung cancer were found plus 491 additional pulmonary nodules (average volume: 40.72 ml, average diameter 4.62 mm). Asbestos-related changes (pleural plaques, fibrosis) were visible in 80 individuals. Lung cancer screening in this high-risk cohort showed a prevalence of lung cancer of 4.28% (8/187) at baseline screening with an additional large number of indeterminate pulmonary nodules. Low-dose MDCT proved to be feasible in this highly selected population.

Aged↗
PubMed2002

Sperm count and chromatin structure in men exposed to inorganic lead: lowest adverse effect levels.

OBJECTIVES: To obtain knowledge on male reproductive toxicity of inorganic lead at current European exposure levels and to establish lowest adverse effect levels, if any. METHODS: A cross sectional survey of the semen of 503 men employed by 10 companies was conducted in the United Kingdom, Italy, and Belgium. The mean blood lead concentration was 31.0 microg/dl (range 4.6-64.5) in 362 workers exposed to lead and 4.4 microg/dl (range below the detection limit of 19.8) in 141 reference workers. Semen volume and sperm concentration were determined in a fresh semen sample according to an agreed protocol subject to quality assurance. The sperm chromatin structure assay (SCSA) was performed at a centralised laboratory. Extraneous determinants including centre, period of sexual abstinence, and age were taken into account in the statistical analysis. If appropriate, possible thresholds were examined by iterative threshold slope linear regression. RESULTS: The median sperm concentration was reduced by 49% in men with blood lead concentration above 50 microg/dl. There was no indication of a linear trend of lower sperm concentration with increasing blood lead values, but threshold slope least square regression identified a blood lead concentration of 44 microg/dl (beta=-0.037, F=4.35, p=0.038) as a likely threshold. Abnormal sperm chromatin structure was not related to blood lead concentration, but some indications of deterioration of sperm chromatin was found in men with the highest concentrations of lead within spermatozoa. Biological monitoring data did not indicate long term effects of lead on semen quantity or sperm chromatin. CONCLUSION: Adverse effects of lead on sperm concentration and susceptibility to acid induced denaturation of sperm chromatin are unlikely at blood lead concentrations below 45 microg/dl. Effects of low level exposure to lead on other measures of testicular function cannot be ruled out.

Adult↗
PubMed2000

Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation.

The epidermal growth factor receptor (EGFR) is overexpressed in about 48% of human breast cancer tissues. To analyse the role of the EGFR in mammary tumor development we generated transgenic mice expressing the human EGFR under the control of either the MMTV-LTR (MHERc) or the beta-lactoglobulin promoter (BLGHERc). The BLGHERc-transgene was expressed exclusively in the female mammary gland, whereas the MHERc transgene was expressed more promiscuously in other organs, such as ovary, salivary gland and testis. Female virgin and lactating transgenic mice of both strains have impaired mammary gland development. Virgin EGFR transgenic mice developed mammary epithelial hyperplasias, whereas in lactating animals progression to dysplasias and tubular adenocarcinomas was observed. In both strains the number of dysplasias increased after multiple pregnancies. The transgene expression pattern was heterogeneous, but generally restricted to regions of impaired mammary gland development. Highest EGFR transgene expression was observed in adenocarcinomas. By using a whole mount organ culture system to study the differentiation potential of the mammary epithelium, we observed a reduced number of fully developed alveoli and a decrease in whey acidic protein expression. Taken together, EGFR overexpression results in a dramatic effect of impaired mammary gland development in vitro as well as in vivo, reducing the differentiation potential of the mammary epithelium and inducing epithelial cell transformation.

Animals↗
PubMed1999

Change in semen quality and sperm chromatin structure following occupational styrene exposure. ASCLEPIOS.

OBJECTIVES: Organic solvents have been suspected to exert detrimental effects on human spermiogenesis. Styrene, which is both mutagenic and neurotoxic, was selected as a suitable organic solvent for further assessment of a possible effect on semen quality and sperm DNA damage. SUBJECTS AND METHODS: Semen samples were collected from 23 reinforced plastics workers at the time of employment and after 6 months of styrene exposure and from 21 nonexposed farmers. Intra-individual changes in conventional semen parameters and sperm-DNA denaturation patterns were related to the internal dose of styrene exposure as measured by postshift urinary mandelic acid. RESULTS: A statistically significant decline in sperm density was seen during styrene exposure from 63.5 to 46.0 million sperm/ml, whereas no decline was seen in the nonexposed subjects. The total sperm count was almost halved from an initial value of 175 million sperm/ejaculate. However, no relationship was apparent when the sperm parameters were related to internal levels of exposure. However, an exposure-response relationship was shown for DNA-denaturation patterns, but the numbers were small. CONCLUSION: A declining sperm count following styrene exposure is suggested. However, the findings of the internal and external comparisons are inconsistent, and this may be due to the high intraindividual variability of semen parameters and the limited study size but may also be attributable to a weak internal exposure gradient. Spermatogenesis may be vulnerable to styrene exposure. However, due to the small numbers these findings are only preliminary.

Adult↗
PubMed1998

Local control of mammary gland differentiation: mammary-derived growth inhibitor and pleiotrophin.

Mammary gland development is controlled by systemic hormones and by growth factors that might complement or mediate hormonal action and provide the signalling basis for mesenchyme-epithelial cross-talk. Two locally expressed factors, pleiotrophin and mammary-derived growth inhibitor (MDGI), their hormonal regulation and proposed functions will be discussed. Pleiotrophin expression in non-tumorigenic, attachment-dependent epithelial cells leads to an attachment-independent, highly tumorigenic phenotype. The fatty acid binding protein MDGI specifically inhibits growth of normal mouse mammary epithelial cells, whereas growth of stromal cells is not suppressed. In mammary gland organ culture, inhibition of ductal growth by MDGI is associated with the appearance of bulbous alveolar end buds and formation of fully developed lobulo-alveolar structures. In parallel, MDGI stimulates its own epithelial-restricted expression and promotes milk protein synthesis. Selective inhibition of endogenous MDGI expression suppresses the appearance of alveolar end buds and lowers the beta-casein level in organ cultures. MDGI activity can be antagonized by epidermal growth factor (EGF); reciprocally, MDGI can suppress the mitogenic effects of EGF. An MDGI-derived C-terminal 11-amino-acid peptide is able to mimic MDGI activity in vitro. In conclusion, members of the family of fatty acid binding proteins are able to regulate mammary gland differentiation locally, and fatty acid binding is not required for this activity.

Amino Acid Sequence↗
PubMed1996

Relation of oestradiol-mediated growth stimulation with the expression of c-erbB-2 protein in xenotransplanted oestradiol-receptor-positive and -negative breast carcinomas.

Attempts were made to correlate growth effects induced by oestradiol and tamoxifen with the hormonal regulation of c-erbB-2 protein in experiments in vivo. We report here the responsiveness of four xenotransplanted oestrogen-receptor(ER)-positive and four ER-negative human mammary carcinomas to oestradiol and tamoxifen. Oestradiol in a dose of 0.5 mg/kg significantly increased the growth of the ER-positive mammary carcinomas 3366, MCF-7, 4134 and 4049, but not the ER-negative tumours 4000, 4296 and MT-3. However, within the group of the ER-negative breast carcinomas the tumour 4151 ES deviates from this growth behaviour, as we could prove an estrogen induced growth. The stimulation of tumour growth by oestradiol was always accompanied by a down-regulation of c-erbB-2 protein both in the ER-positive mammary carcinomas and in the ER-negative mammary carcinoma 4151 ES. Tamoxifen significantly inhibited the growth of the ER/PR-positive mammary carcinomas 3366 and MCF-7 but not the ER-positive/PR-negative mammary carcinomas 4049 and 4134. In the group of ER-negative mammary carcinomas only the growth of the oestrogen-responsive tumour 4151 ES was significantly inhibited by tamoxifen. The inhibition of tumour growth by tamoxifen was correlated with a reversion of the oestradiol-induced down-regulation of c-erbB-2, also in the ER-negative/oestradiol-responsive mammary carcinoma 4151 ES. From our results we hypothesize that the oestrogen-dependent growth of ER-negative breast carcinoma 4151 ES could also be correlated with the oestradiol-regulated expression of c-erbB-2 protein.

Animals↗
PubMed1996

[C-erbB-2, PCNA and histomorphologic factors in breast carcinoma after oral contraceptive use].

The influence of oral contraceptives (OC) on histomorphological and molecular biological prognostic factors was studied in 471 breast cancer patients. Differences in histological tumor type, histological grade, tumor size, lymph node status, hormonal receptor status, PCNA expression and c-erbB-2 protein overexpression were investigated in relation to the duration of OC use (< 5 years/ > or = 5 years) and the time since last use. A total of 297 (63%) patients had used oral contraceptives at some time in their life; 186 patients (39.5%) had used OC's for 5 years or more. There were no significant differences in the tumor characteristics investigated with respect to OC use in general. Neither long-term use at some time in their life nor long-term use until breast cancer diagnosis had an effect on histomorphological and molecular biological factors. Thus, steroid hormones contained in OC's had no direct effect on prognostic factors in breast cancer.

Adult↗
PubMed1995

Scatter factor/hepatocyte growth factor is essential for liver development.

Polypeptide growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor/hepatocyte growth factor (SF/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood proteinase plasminogen. The cellular responses of SF/HGF are mediated by the c-Met tyrosine kinase receptor. Here we report that mice lacking SF/HGF fail to complete development and die in utero. The mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta, particularly of trophoblast cells, is impaired. Thus, SF/HGF is essential for the development of several epithelial organs.

Animals↗
PubMed1995

EGF and TGF alpha modulate structural and functional differentiation of the mammary gland from pregnant mice in vitro: possible role of the arachidonic acid pathway.

Epidermal growth factor (EGF) has been suggested to be involved in mammary gland development by mitogenic stimulation of the ductal and alveolar epithelium in virgin mice. The present studies demonstrate that also in late-pregnant mice EGF leads to proliferation of the ductal, ductular, and alveolar epithelium. The mitogenic effect is associated with structural and functional dedifferentiation of alveolar cells as revealed by analysis of morphology, expression of cytosolic and secretory proteins, and fatty acid synthesis. Using a combination of metabolic inhibitors, the dedifferentiating effect of EGF could be blocked while the mitogenic action was not influenced. This finding demonstrates that the signal transduction pathway leading to dedifferentiation and mitosis can be separated, and that the dedifferentiating effect of EGF is independent of its mitogenic properties, but is probably mediated by activation of the arachidonic acid-dependent pathways (cyclo- and lipoxygenase pathways). Release of arachidonic acid from the endogenous phospholipid pool was found to be an early response of the explants to EGF. Accordingly, arachidonic acid itself proved to be capable of inducing epithelial dedifferentiation but failed to stimulate proliferation. TGF alpha showed qualitatively similar effects as EGF but was generally a stronger agonist. It is suggested that EGF and TGF alpha also play a role in mammary gland physiology during pregnancy by final developing and maintenance of the lobulo-alveolar structure in the mammary gland and prevention of premature onset of lactation, and that this is mediated through the PLA2-arachidonic acid signalling cascade.

Animals↗
PubMed1995

Antiprogestins inhibit growth and stimulate differentiation in the normal mammary gland.

Antiprogestins possess a potent antitumor activity in hormone-dependent experimental breast cancer models. Though the underlying mechanism is not clear, induction of functional differentiation seems to be a major event. This study attempts to test directly for antiproliferative and differentiation promoting activities of antiprogestins on the normal mammary gland. To this end, whole organ cultures of mammary glands from estradiol/progesterone-primed virgin mice maintained in a serum-free medium with aldosteron, prolactin, insulin, and hydrocortisone were exposed to the antiprogestin ZK114043. A 4-day treatment of organ cultures led to a strong inhibition of epithelial DNA synthesis. In parallel, ZK114043 caused alveolar cells to acquire a more differentiated phenotype distinguished by secretory active alveoli composed of single cell layers with increased fat droplet accumulation and enhanced expression of the milk proteins beta-casein and whey acidic protein (WAP). Particularly strong effects were found on the expression of mammary-derived growth inhibitor (MDGI). Both half-maximal inhibition of epithelial DNA synthesis and stimulation of MDGI mRNA expression were found at about 5 ng/ml of ZK114043. Presence in the medium of 5 micrograms/ml hydrocortisone rendered antiglucocorticoid effects of ZK114043 highly unlikely. Furthermore, prevention of action of ZK114043 by the progesterone agonist R5020 and ZK114043 stimulated expression of beta-casein and MDGI mRNA in cultured glands of 10-week-old unprimed virgin mice suggest a progesterone receptor-mediated mechanism of antiprogestin action. Two other antiprogestins, Mifepristone and Onapristone, likewise stimulated MDGI expression. The data provide direct evidence that antiprogestins act like a differentiation factor in the normal mammary gland.

Animals↗
PubMed1995

Prognostic value of proliferating cell nuclear antigen and c-erbB-2 compared with conventional histopathological factors in breast cancer.

Expression of proliferating cell nuclear antigen (PCNA) and c-erbB-2 oncoprotein has been assessed in 471 women with breast cancer to evaluate their prognostic value as compared to conventional histopathological factors. In univariate analysis, high PCNA expression (> or = 20%) predicted a significantly worse survival in lymph-node-negative tumors (univariate P = 0.031). However, the effect disappeared in multivariate analysis and the histological grade remained the only independent factor for this group. Despite its close correlation to histological grade (P < 0.001), PCNA expression discriminated subsets with different survival within the heterogeneous group of moderately differentiated tumors (univariate P = 0.073, multivariate P = 0.075). PCNA expression was not found to be a significant prognostic factor in lymph-node-positive tumors, thus it was of limited value for breast cancer patients as a whole. c-erbB-2 protein overexpression was associated with a worse survival (univariate P = 0.019, multivariate P = 0.057) for the entire group of patients. The effect was mainly attributed to the significance of c-erbB-2 as an independent factor in lymph-node-positive (up to three nodes, multivariate P = 0.04; four or more nodes: multivariate P = 0.017) and large tumors (> 2 cm: multivariate P = 0.002). c-erbB-2 was without significance in lymph-node-negative patients. Though both factors might amplify the prognostic information for distinct patient subsets they do not achieve the strong prognostic value of conventional histopathological features in breast cancer.

Adult↗
PubMed1995

Histochemical localization of heart-type fatty-acid binding protein in human and murine tissues.

Cellular fatty acid-binding proteins (FABP) are a highly conserved family of proteins consisting of several subtypes, among them the mammary-derived growth inhibitor (MDGI) which is quite homologous to or even identical with the heart-type FABP (H-FABP). The FABPs and MDGI have been suggested to be involved in intracellular fatty acid metabolism and trafficking. Recently, evidence for growth and differentiation regulating properties of MDGI and H-FABP was provided. Using four affinity-purified polyclonal antibodies against bovine and human antigen preparations, the cellular localization of MDGI/H-FABP in human and mouse tissues and organs was studied. The antibodies were weakly cross-reactive with adipose tissue extracts known to lack H-FABP, but failed to react by Western blot analysis with liver-type FABP (L-FABP) and intestinal-type FABP (I-FABP). MDGI/H-FABP protein was mainly detected in myocardium, skeletal and smooth muscle fibres, lipid and/or steroid synthesising cells (adrenals, Leydig cells, sebaceous glands, lactating mammary gland) and terminally differentiated epithelia of the respiratory, intestinal and urogenital tracts. The results provide evidence that expression of H-FABP is associated with an irreversibly postmitotic and terminally differentiated status of cells. Since all the antisera employed showed spatially identical and qualitatively equal immunostaining, it is suggested that human, bovine and mouse MDGI/H-FABP proteins share highly homologous epitopes.

Animals↗
PubMed1995

[C-erbB-2, EGF receptor, p53 and PCNA. The prognostic significance of recent tumor markers for lymph node negative breast cancer].

In 216 breast cancer patients, the prognostic value of current biological factors (c-erbB-2, EGF-receptor, p53, PCNA-proliferative fraction) was compared with that of conventionally histomorphologic features (histologic type, histologic grade, tumour size, hormonal receptor status). After a 66(6 - 109) months' median follow-up survival was significantly correlated with histological grade (p = 0.014) and PCNA-proliferative activity (p = 0.015). The prognostic influence of oestrogen receptor (ER)- and progesteron receptor (PR-)status achieved borderline significance (ER/p = 0.07; PR/p = 0.05). Neither c-erbB-2, EGF-R, p53 nor any of the other factors showed any correlation to survival. In the multivariate analysis, histological grade was revealed as the only independent prognostic factor. The prognostic value of PCNA was second to histological grade and if grade was excluded from the analysis, PCNA-expression became the only independent factor. Thus, in individual cases the PCNA-proliferative fraction could help the clinician to decide on the therapy.

Adult↗
PubMed1994

Significance of immunohistochemical c-erbB-2 product localization pattern for prognosis of primary human breast cancer.

Concerning immunohistochemistry of the c-erbB-2 receptor in human mammary carcinoma, membranous immunostaining of tumor cells has been generally considered as a potential risk factor for early recurrence, whereas cytoplasmic reactivity has been neglected. An archival study on 463 patients with primary breast cancers demonstrates that cytoplasmic localization of p185 is significantly correlated with high estrogen and progesterone receptor levels, low histological grade and a low proliferating tumor cell fraction. In accordance with these data, patients bearing mammary carcinomas with cytoplasmic localization of p185 reactivity have a significant better overall survival than those with membranous immunostaining.

Breast Neoplasms↗
PubMed1994

Establishment and characteristics of two new human mammary carcinoma lines in nude mice with special reference to the estradiol receptor status and the importance of stroma for in vivo and in vitro growth.

Two new human mammary carcinoma lines originating from surgical material were established in nude mice. According to the adopted criteria, the tumor 4049 has been classified as estradiol receptor positive and mammary carcinoma 4296 as estradiol receptor negative. Both tumors proved to be c-erbB-2 protein positive and EGF-receptor negative. In contrast to carcinoma 4296, the in vitro growth and the take rate of mammary carcinoma 4049 in nude mice seems to be dependent on stromal components. Pretreatment of mice with estradiol/peanut oil before tumor engraftment was an essential precondition for the growth of the primary tumor in nude mice. After successful establishment the tumor growth was significantly stimulated by estradiol. The growth rate of mammary carcinoma 4296 was independent of any supplementation of estradiol. The two breast tumors were characterized with regard to their growth behaviour, histology, and sensitivity to cytostatics and antihormones. They are considered suitable tumor models for the testing of antineoplastic substances and for biological experiments.

Animals↗
PubMed1994

C-erbB-2 overexpression in primary breast cancer: independent prognostic factor in patients at high risk.

The prognostic value of c-erbB-2 protein overexpression has been evaluated in 463 patients with operable breast cancer after a median follow-up of 66 months. Overexpression was observed in 99/463 (21%) of the breast tumors. It showed significant positive correlation to histological grade (p < 0.0001) and tumor size (p < 0.02). A relationship of borderline significance was observed between c-erbB-2 protein overexpression and negative or low estrogen receptor (ER) content. No significant correlation was found to lymph node involvement or proliferating tumor cell fraction as determined by the proliferating cell nuclear antigen (PCNA). After a median follow-up of 66 months (range 6 to 109 months), the overall survival of all patients amounted to 63%. Multivariate analysis revealed lymph node involvement, tumor size, histological grade, histological type, c-erbB-2 protein overexpression, progesterone receptor (PR) content, and oral contraceptive use as independent prognostic factors. In an univariate analysis, the overall survival amounted to 72% and 38% of tumor patients with negative and positive c-erbB-2 protein overexpression, respectively. The most significant finding is that c-erbB-2 overexpression has been recognized as an independent predictive factor in subsets of tumor patients who would be expected to have a generally poor prognosis, such as those indicating axillary lymph node involvement, large tumor size (> 2 cm), and PR negativity.

Adult↗