Biomedical subjects

C Häckel

Publications and source records attributed to C Häckel.

10 recordsLinked to original sources

PubMed2000

Cathepsin K expression in human lung.

Tissue remodeling is crucial in different lung diseases, in the embryonal development as well as in bronchial carcinoma. Cathepsins were proposed to be involved in the degradation of matrix proteins. Cathepsin K is one of the most potent matrix-degrading cysteine proteinases known as yet. The elastinolytic and collagenolytic activity of this papain-like protease is comparable with that of neutrophil elastase. We have investigated the cathepsin K expression in normal adult lung tissues, in embryonal lung tissue and in bronchial carcinoma. With help of specific anti-cathepsin K antibodies it could be shown that cathepsin K was expressed in bronchial epithelial cells. These data could be confirmed at mRNA level using a quantitative RT-PCR as well as by visualisation of the specific enzymatic activity in epithelial cell lines. During the embryonal development cathepsin K was expressed in the epithelial cells of the developing bronchi. The expression seemed to be upregulated in parallel with the development of the bronchial and alveolar lumen. In the later phase of lung development the cathepsin K expression was restricted to bronchial epithelial cells. Furthermore, using quantitative RT-PCR it could be shown that cathepsin K-mRNA was upregulated in lung tumor tissues in comparison to normal tissues from the same patients. These data suggest that cathepsin K may play an important role in matrix remodeling of the lung under physiological and pathological conditions.

Bronchi↗

PubMed2000

Mdm2 gene amplification in gastric cancer correlation with expression of Mdm2 protein and p53 alterations.

Mdm2, localized on chromosome 12, is considered a negative regulator of p53 function and seems to play a role in the pathogenesis of a variety of tumors. The mdm2 amplification in advanced-stage gastric carcinoma has not yet been investigated. Mdm2 amplification was determined in 43 gastric carcinomas, and the genetic results were correlated with mdm2 protein expression, p53 alterations, and clinicopathologic data. The tumors were classified according to Lauren: 20 intestinal-type tumors, 19 tumors of diffuse growth inclusive of a primary small cell carcinoma, and 4 carcinomas with mixed differentiation. Staging was based on the pTNM classification system. Mdm2 and p53 were demonstrated by immunohistology on formalin-fixed and paraffin-embedded tumor tissue. The mdm2 oncogene was amplified by nonradioactive hybridization of tumor DNA with an mdm2 cDNA probe. The Southern blots were evaluated densitometrically. For p53 mutation screening, we analyzed the highly conservative regions of the p53 gene (exons 4 to 8) with the use of the polymerase chain reaction-single-strand conformation polymorphism technique. Polymerase chain reaction products with band shifting were directly sequenced. Mdm2 amplification was demonstrated in 18 tumors (41.8%). The mdm2 gene was amplified more frequently in carcinomas with a diffuse growth pattern. Gastric carcinomas of the intestinal type, however, showed a higher frequency of p53 alterations. There was no statistical significance of the molecular genetic and immunohistologic results of the mdm2/p53 status to staging as well as to age and sex of the patients. The mdm2/p53 pathway is a part of the carcinogenesis of gastric carcinoma. Only approximately 20% of gastric carcinomas failed to show mdm2 and/or p53 alterations. The upregulation of the mdm2 oncogene and the accompanying inactivation of the tumor suppressor gene 53 seem to play a role above all in carcinomas of the diffuse type.

Adult↗

PubMed2000

Hormonal regulation of neonatal weight: placental leptin and leptin receptors.

OBJECTIVE: To examine whether umbilical and maternal leptin levels correlate with birthweight, placental weight, and maternal weight; and to detect membrane-bound leptin receptors in placental tissue as well as soluble leptin receptors in umbilical and maternal blood. DESIGN: Prospective observational study. SETTING: University teaching hospital. METHODS: Serum levels of leptin and soluble leptin receptors were analysed in 31 randomly selected mother/newborn pairs at delivery. In addition, placental tissue was assayed for leptin receptors using immunocytochemistry and Western blot. RESULTS: The mean [SD] leptin level in umbilical cord venous blood (7.1 ng/mL [4.0]) was significantly lower (P<0.001) than in maternal blood (22.5 ng/mL [10.8]). Umbilical cord leptin concentrations correlated significantly with birthweight (P<0.001), placental weight (P<0.005) but not with maternal leptin. Maternal leptin concentrations correlated only with maternal weight (P<0.001). In chorionic villous tissue, trophoblasts stained strongly positive for leptin receptor-like immunoreactivity. Two membrane-bound isoforms of the leptin receptor were also detected in placental tissue. In both umbilical and maternal serum, a soluble leptin receptor was found migrating as broad band at Mr 97,000 D. CONCLUSION: The present data strongly reinforce the idea that circulating leptin levels may provide a growth-promoting signal for fetal development during late pregnancy. While membrane-bound leptin receptors may be involved in autocrine regulation of placental leptin production, the soluble receptor form may serve as a transport vehicle for leptin to fetal tissues.

Adult↗

PubMed2000

Telomerase activity and expression of hTRT and hTR in gastrointestinal stromal tumors in comparison with extragastrointestinal sarcomas.

Stromal tumors of the gut (GISTs) have rarely been analyzed for genetic alterations. This study aimed at determining telomerase activity and the expression of the telomerase subunits human telomerase reverse transcriptase (hTRT) and human telomerase RNA (hTR) in GISTs and extragastrointestinal neurogenic or myogenic sarcomas. Telomerase activity was investigated using the telomeric repeat amplification protocol assay in 21 GISTs, recurrences and liver metastases from 16 patients, and in 22 leiomyosarcomas and 21 malignant peripheral nerve sheath tumors (MPNSTs), which served as reference tumors. Expression of hTRT and hTR mRNA was investigated using reverse transcription-PCR. Thirteen GISTs were localized in the stomach and three in the small intestine. Two tumors were benign. In one case, the biological behavior was uncertain. In 67% of GISTs, high telomerase activity was found, whereas high activity was noted in only 18% of leiomyosarcomas and in 48% of MPNSTs. There was no activity in two benign and two malignant GISTs. In one malignant tumor of the small intestine, the primary tumor showed no activity at first but a marked activity in its recurrence. In the tumor with uncertain behavior, telomerase activity and hTRT expression were only weak. In all GISTs showing telomerase activity, the catalytic subunit hTRT was expressed. All GISTs and extragastrointestinal sarcomas expressed hTR. In comparison with leiomyosarcomas and MPNSTs, malignant GISTs showed a higher telomerase activity, which, however, was not seen in benign GISTs. It is possible that telomerase activity occurs during the progression of malignant GISTs. There was a correlation between telomerase activity and the expression of hTRT.

Adult↗

PubMed1999

Expression of cathepsin K in lung epithelial cells.

Alveolar and bronchial epithelial cells have been shown to have regulatory functions in the maintenance of lung structure and function. Recent evidence supports the premise that these cells can synthesize a variety of extracellular matrix components in vitro, suggesting an active participation in connective tissue remodeling. Their possible role in extracellular matrix degradation, however, is less clear. This study addresses the question of whether alveolar and bronchial epithelial cells express the highly collagenolytic and elastinolytic cysteine proteinase cathepsin K, which has recently been newly described. We provide evidence that the epithelial cell lines A549 and BEAS-2B are capable of expressing cathepsin K messenger RNA. Furthermore, we show that cathepsin K is expressed in normal bronchial epithelial cells. Western blot analyses of human lung-tissue lysates revealed specific immunoreactivity at molecular weights of 46 and 27 kD, corresponding to the procathepsin and the mature cathepsin K. Immunohistochemical analyses showed a pronounced staining of bronchial epithelial cells and in single alveolar epithelial cells. Using a specific fluorogenic cytochemical assay, the intracellular activity of the enzyme was localized. These findings demonstrate that bronchial and alveolar epithelial cells are capable of expressing cathepsin K, which could be of considerable importance for remodeling processes of the extracellular matrix in the lung.

Bronchi↗

PubMed1999

[New findings in orthopedic pathology].

The term orthopedic pathology refers to bone- and joint-affecting diseases which are important for the orthopedic surgeon. In the report presented here, emphasis is placed on the membrane-associated proteolysis, which is essential for the degradation of the extracellular matrix. Matrix-degrading processes play a role not only in arthrosis but also in rheumatoid arthritis. Moreover, they are strongly associated with the problem of loosening of protheses, which is of utmost importance for the orthopedic surgeon. In these processes, major roles are played by the plasminogen activator system, plasmin, different matrix metalloproteinases, including the membrane type matrix metalloproteases and different cathepsins. A deeper insight into the function of these proteins and their influence on the matrix degradation in joint diseases will open the way for new diagnostic and therapeutic strategies. Investigations into a large number of chondrosarcomas have shown that for this type of bone lesions, urokinase plasminogen activator and cathepsin B are prognostic parameters that are independent of the differentiation grade. Also, in this context, investigations into the membrane-bound proteases will be of great practical and diagnostic value.

Arthroplasty, Replacement↗

PubMed1998

The pS2 protein in colorectal carcinomas and metastases.

Expression of pS2 protein in 50 primary tumors, metastases and recurrent tumors of colorectal carcinomas has been analyzed by immunohistochemistry. Sixty percent of the primary tumors were at least focally positive for the antigen. There was no correlation between pS2 expression and histologic grade of the lesions. In contrast, pS2 expression in T4 and T3 tumors was significantly higher than in T2 carcinomas. Immunoreactions in carcinomas with distant metastases (MI) were stronger than in M0 cases. However, this difference did not reach statistical significance. The presence of lymph node metastases did not correlate with pS2 expression. High expression of pS2 in T4 and T3 carcinomas together with the finding of pronounced expression of the antigen at invasion fronts in single cases could be interpreted as a function in tumor cell invasion and motility. However, in metastases and recurrent tumors, pS2 expression did not differ from primary lesions (53% positive lesions). All in all, under consideration of the latter finding in particular and together with the randomly distributed immunopositive tumor cells and cell clusters in the majority of cases, it is more likely that the expression pattern of pS2 in colorectal carcinomas is a result of overall tumor cell heterogeneity.

Carcinoma↗

PubMed1997

Expression of plasminogen activators and plasminogen activator inhibitor 1 in dedifferentiated chondrosarcoma.

BACKGROUND: The plasminogen activator system plays an important role in different malignant tumors. These enzymes participate in the destruction of intercellular matrices and basement membranes and/or can modulate the growth potency of tumor cells and may even promote metastases. In this study, the expression of three glycoproteins that play a role in the plasminogen activator system as activators of proteolysis-urokinase type plasminogen activator (u-PA), tissue type plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1) were studied in various components of dedifferentiated chondrosarcomas of bone. METHODS: The expression of u-PA, t-PA, and PAI-1 was investigated in 10 dedifferentiated chondrosarcomas and 14 conventional chondrosarcomas. The plasminogen activator/inhibitor glycoproteins were visualized immunohistochemically on paraffin sections and the levels of expression were assessed semiquantitatively. RESULTS: In dedifferentiated chondrosarcoma, high grade dedifferentiated components displayed strong, diffuse coexpression of u-PA, t-PA, and PAI-1. For all glycoproteins studied, the immunoreactivity was significantly increased compared with the reactions in the low grade cartilaginous component of the same tumor and conventional chondrosarcoma. In the latter, u-PA, t-PA, and PAI-1 expression was found to be enhanced at invasive foci and in regions of endochondral ossification. CONCLUSIONS: The current study documents the overexpression of u-PA, t-PA, and PAI-1 in dedifferentiated chondrosarcoma and suggests involvement of the plasminogen activator system in the biology of these tumors.

Bone Neoplasms↗

PubMed1997

Expression of P-glycoprotein in high grade osteosarcomas with special emphasis on chondroblastic subtype.

The development of chemoresistance is one of the major clinical problems in the therapy of malignant bone tumors in childhood. The expression of membrane-bound P-glycoprotein turned out to be an essential factor in the evidence of resistant tumor cells. To investigate the significance of multidrug resistance in the prognosis of highly malignant osteosarcomas, the immunohistologic expression of P-glycoprotein was investigated in the tumor tissue of 52 patients under special consideration of the histologic subtype. The data were compared with the histologic regression grade in the resection specimen and correlated with clinical data. Formalin-fixed, paraffin-embedded tissue and, additionally, fresh frozen material taken from the primary biopsy were stained using monoclonal antibody JSB1. 29 (55%) of the tumors investigated were P-glycoprotein positive. Considering the response to chemotherapy, no conclusion could be drawn regarding P-glycoprotein expression, regression grade in the resection specimens, and the clinical follow-up. P-glycoprotein was detected in only 52% of the non-responders. A positive reaction was also evidenced in 59% of the patients with high chemosensitivity. A comparison of the histologic subtypes yielded a significant result in the chondroblastic osteosarcomas. 11 of 12 cases showed a strong expression of P-glycoprotein. Most of the cases were non-responders, and using Kaplan-Meier live tables, an unfavorable clinical outcome could be demonstrated. Possibly, chondroblastic tumors have a special position among osteosarcomas because of their differentiation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

The urokinase plasminogen activator (u-PA) and its inhibitor (PAI-1) in embryo-fetal bone formation in the human: an immunohistochemical study.

The role of urokinase plasminogen activator and plasminogen activator inhibitor-1 in human embryo-fetal bone formation between the 9th and the 20th week of gestation has been studied immunohistochemically. While mature osteocytes of the secondary spongiosa and resting chondrocytes of the bone epiphyses were negative for both antigens in each developmental stage, metabolically active parts of the osseocartilaginous system showed a strong immunoreactivity. Until the end of the 10th week of gestation urokinase plasminogen activator and plasminogen activator inhibitor-1 could not be demonstrated in the shaft of the preexisting cartilaginous models of bones, which correlates with the morphological developmental stage of the embryos. Later, osteoblasts and chondrocytes in the areas of enchondral ossification, and the perivascular chondrocytes of the epiphyseal secondary ossification centres, showed similarly high concentrations of urokinase plasminogen activator and plasminogen activator inhibitor-1. Moreover, the individual ossification stages of the different bones in embryo-fetal development could be demonstrated immunohistochemically. While humeri and femora showed diaphyseal immunoreactivities at an early stage, positive reactions in the phalanges were found only much later. Thus, the enzymes of the fibrinolytic system studied are clearly involved in the desmal and enchondral ossification process in the osseocartilaginous compartment.

Bone and Bones↗