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Biomedical subjects

K Havemann

Publications and source records attributed to K Havemann.

At least 145 records · Page 8Linked to original sources
PubMed1988

Detection of granulocyte elastase specific IgG split products in rheumatoid synovial fluid.

In vitro granulocyte elastase is known to cleave a large number of substrates e.g. complement components, fibrinogen, collagen and IgG. In vivo the enzyme is rapidly complexed by the plasma inhibitors a1proteinase inhibitor (a1PI) and a2macroglobulin. Therefore in biological fluids elastase is measured as the inactive a1PI-complex. We present a radioimmunoassay for elastase specific IgG split products as marker for the elastase activity in vivo. Elastase splits human IgG1 in Fab and Fc fragments and low molecular weight peptides. We produced specific antibodies against the elastase induced Fc fragment by immunization with an elastase generated peptide. After purification of the antibodies there is no crossreactivity with native IgG nor with similar Fc fragments produced by plasmin or papain. The elastase specific IgG split products are detected in synovial fluid samples of patients with rheumatoid arthritis. The measured concentrations are higher in the RA group than in control groups of patients with other inflammatory joint diseases.

Arthritis, Rheumatoid↗
PubMed1988

Peptides and growth factors in small cell lung cancer: production, binding sites, and growth effects.

We investigated the production, binding to cell membranes, and influence on cell proliferation of peptides and growth factors in 4 classic, 5 transitional, and 5 variant SCLC cell lines. Glucagon, neurotensin, and TGF-alpha were present in all cell lines. Bombesin was predominantly found in classic cell lines and insulin in variant cell lines. Neurokinin A, calcitonin, CGRP, GHRF, somatostatin, and CNTF were detectable in some cell lines without prevalence for a particular cell type. We could not detect AVP, growth hormone, neuropeptide Y, substance P, VIP, and NGF. Insulin binding sites were present on 11/14 cell lines, and some cell lines specifically bound bombesin, calcitonin, and EGF. Growth effects were detectable for insulin, GRP-related peptides, tachykinins, and VIP. Using serum-free conditions, insulin and VIP had a growth stimulating effect in liquid culture at nanomolar concentrations. Bombesin and neuromedin B stimulated the clonal growth at a concentration of 3-30 nM. The tachykinins neurokinin A, neurokinin B, physalaemin, and eledoisin inhibited the clonal and mass culture growth with a peak effect in the range of 0.1 to 10 pM. Peptide-induced stimulating and inhibiting effects were within a magnitude of 2-fold. All other peptides and growth factors tested, including ACTH, AVP, calcitonin, glucagon, neurotensin, somatostatin, EGF, CNTF, and NGF did not affect the growth of SCLC. We conclude that the growth of SCLC is partly controlled by such peptides in an autocrine/paracrine fashion.

Amino Acid Sequence↗
PubMed1988

Multiple myeloma of the serosa coat.

We report on a 47-year-old male patient with IgA-kappa plasmacytoma, who 12 months subsequent to diagnosis developed marked ascites. On light and electron microscopy morphologically identical plasma cells with bizarre intracytoplasmatic material were found in the bone marrow, pleural exudate, and ascites fluid. This kind of extramedullary spread is extremely rare and usually resists therapy. The mean survival rate for the 9 patients with malignant plasmacellular ascites whose cases have been documented so far was 2 months. After progression under VCMP regimens our patient has been successfully treated over a period of more than 4 years with i.v. VP16 monotherapy with additional intermittent local administration of methotrexate and systemic poly-chemotherapy according to the VAD scheme.

Adult↗
PubMed1988

Production of immunoreactive insulin-like growth factor I and response to exogenous IGF-I in small cell lung cancer cell lines.

Small cell lung cancer (SCLC) cell lines were examined for the presence of insulin-like growth factor I-related protein (IGF-I) in cell pellets and culture media. IGF-I immunoreactivity was detected in 11/14 pellets, ranging from 12 to 76 mIU/mg soluble protein. The IGF-I levels in the cell pellets showed a correlation to the corresponding culture media. IGF-I binding sites were found in all tested cell lines. The maximum binding (Bmax) ranged from 131 to 1230 fmol/mg protein and the dissociation constant (KD) from 0.89 to 5.21 nM. The incorporation of [3H]thymidine in the presence of recombinant human IGF-I resulted in a clearly increased DNA synthesis in two of seven cell lines. Thus, IGF-I may be an important growth factor in SCLC.

Animals↗
PubMed1988

Peptide hormones in patients with acute leukaemia.

Paraneoplastic production and secretion of peptide hormones by numerous malignant tumours is a well-known phenomenon. The incidence of the production of six peptide hormones was evaluated in patients with acute leukaemia. Most often the calcitonin gene-related peptides were found to be elevated in sera at the time of diagnosis. The values evaluated for the hormones were: h-CT 46.7%, CGRP 51%, s-CT 20.7%, PTH 15.7%, beta-HCG 15%, and ACTH 11.6%. A significant coincidence of two or more hormones was not observed. In 83.4% of the patients increased concentrations of at least one of the six hormones were found. Clinical and biochemical parameters showed no influence on the serum levels of these peptides. Analysis of elevated hormone serum levels in subtypes of leukaemia revealed that the calcitonin-related hormones were significantly correlated to more immature forms of leukaemia such as AUL and M1. Synthesis of calcitonin gene-related peptides was also seen in established leukaemic cell lines and in buffy coat cells of untreated patients with acute leukaemia. This investigation provides further evidence that peptide hormone production in leukaemic blasts is a common finding. These results further suggest hormone production to be a universal concommitant of neoplasia. A possible influence of these peptide hormones on the biological behaviour of the malignant cells is discussed.

Acute Disease↗
PubMed1988

Characterization of the state of differentiation of six newly established human non-small-cell lung cancer cell lines.

Six new non-small-cell lung cancer (NSCLC) cell lines were established directly from human tissue or indirectly via nude mouse xenografts in serum-supplemented media with success rates of 8% and 13%, respectively. They comprised one adenocarcinoma (ADLC-5M2), two squamous cell carcinomas (EPLC-32M1, EPLC-65H), two large cell carcinomas (LCLC-97TM1, LCLC-103H), and one malignant biphasic mesothelioma (MSTO-211H). All cell lines grew adherent to culture vessels with population doubling times (PDT) of 16-40 h, formed colonies in soft agarose with efficiencies of 0.1%-5.1%, and all grew in athymic nude mice. Xenograft histologies appeared as follows: (a) undifferentiated carcinomas with feeble resemblance to the original tumors in the case of adenocarcinomas and squamous cell carcinomas; (b) large cell carcinoma with high resemblance to the original tumor; (c) an undifferentiated tumor with predominance of large epithelial cells and few fibrous cells in the case of mesothelioma. Human chorionic gonadotropin (HCG) was found by radioimmunoassay and high-affinity binding sites for epidermal growth factor (EGF) by radio-receptor assay in 4/4 cell lines. A very low activity of L-DOPA decarboxylase (DDC) was detectable only in the adenocarcinoma cell line. All cell lines overexpressed the c-myc protooncogene, and no gene rearrangement or amplification was observed. Chromosome analysis revealed modal chromosome numbers of 70-73 in ADLC-5M2, EPLC-32M1, EPLC-65H, and MSTO-211H. Cell lines derived from large cell carcinoma had modal values of 65 and 170 and a wider chromosome distribution than all other cell lines. A NSCLC specific chromosomal aberration has been undetectable until now. These cell lines may aid in elucidating the biology of NSCLC and its interrelationship to other lung tumors.

Animals↗
PubMed1988

Calcitonin-related peptides in patients with acute leukemia: association of human calcitonin with poor prognosis.

Elevated serum levels of peptides hormones in patients with acute leukemia and production of these agents by the leukemic blasts have been described. In 77 patients with acute leukemia the influence of common risk factors and elevations of serum levels of calcitonin-related peptides on clinical outcome was evaluated. By multivariate analysis, only age and elevated serum level of h-CT were found to be significantly correlated to survival. CGRP and s-CT showed no influence on outcome. Closer inspection of the clinical course of these patients showed that patients with elevated h-CT are not likely to survive the first 4 weeks after diagnosis. The possibility that this hormone may influence the biological behavior of the leukemic cells is discussed.

Acute Disease↗
PubMed1988

[Results of 2 multicenter therapy studies in inoperable non-small cell bronchial cancer].

A total of 166 patients with non-small cell lung cancer (NSCLC) were included in two multicenter trials testing different treatment regimens. In study I, 116 patients received 4 cycles of aggressive polychemotherapy consisting of cis-platinum 100 mg/m2 (day 1), etoposide 100 mg/m2 (days 4-6), and vindesine 3 mg/m2 (day 1) (CEV); patients without distant metastases subsequently received chest irradiation with 50 Gy. In study II, 50 patients were treated with monochemotherapy consisting of etoposide 250 mg/m2 (days 1-3), and ifosfamide 5 g/m2 as 24-h infusion (day 29). While this program was repeated in responders with extensive disease (ED), patients with limited disease (LD) subsequently received chest irradiation with 50 Gy using 20 mg/m2 cis-platinum weekly as a radiosensitizer. Response rates (CR + PR) to chemotherapy were higher in study I than in study II, and were 26% (CR 3%) vs. 8% (CR 0%) for all patients, 18% (CR 0%) vs. 4% (CR 0%) for ED, and 45% (CR 11%) vs. 13% (CR 0%) for LD. The increase in response rates by radiotherapy was marginal in study I (CR + PR 47%, CR 18%), but remarkable in study II (CR + PR 42%, CR 29%). While median survival was slightly longer in study I than in study II for ED (7.7 vs. 6.6 months) and LD (14.4 vs. 12.0 months), the 2-year survival rate was in favor of study II (10% vs. 25%). Toxicity was clearly more pronounced in study I, including 3 lethal complications and 16 discontinuations of therapy due to side effects or refusal. Thus, while in ED the efficacy of both treatment regimens was very restricted, in LD radiotherapy with cis-platinum as a radiosensitizer achieved a relatively high 2-year survival rate which justifies further testing of this treatment strategy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Neoantigenic group on Fc fragments in rheumatoid arthritis synovial fluids.

Expression of neoantigens during denaturation of IgG by oxygen radicals or proteolysis was assumed to be a possible mechanism for stimulation of rheumatoid factor (RF) formation and/or granulocyte dependent inflammative joint destruction. The so-called human leukocyte elastase (HLE) regularly released by stimulated neutrophils f.e. into the RA synovial fluid is known to split IgG in vitro into papain like fragments and low molecular weight peptides. The n-terminal site of the HLE related Fc is bearing a neoantigenic group which is located near the hinge region but not expressed by the native IgG. The neoantigen itself is represented by the low molecular weight peptides produced by prolonged HLE-IgG proteolysis. Detection of HLE generated Fc in synovial fluids was performed by radioimmunoassay specific for the neoantigen. Patients were divided into the three groups; I RA (n = 23), II inflammative joint effusions except RA (n = 23), III osteoarthritis and trauma (n = 19). The biological effect of the neoantigen on to granulocyte oxidative metabolism was tested by Cytochrome C reduction and chemiluminescence. Neoantigen bearing Fc could be detected in 15 of 23 cases of group I, in group II in 11 of 23 cases and only in 7 of 19 cases in group III. The median concentrations were 0.62 micrograms in group I and zero in II and III. The HLE derived Fc were able to inhibit the oxidative metabolism of activated granulocytes in vitro. The O2- production of stimulated granulocytes was depressed dose dependent by the neoantigen. The neoantigenic group itself does not react with RF as proved by nephelometric titration of HLE derived Fc, neoantigenic peptide and native IgG against a RF standard.

Antigens↗
PubMed1988

Influence of recombinant human granulocyte-macrophage colony-stimulating factor on granulocyte functions.

Besides its effect on bone marrow progenitors, GM-CSF is able to interact with mature cells such as granulocytes which express GM-CSF receptors at their surface. Using an incubation period of 90 min, which corresponds to the maximum expression of GM-CSF receptors, we studied oxidative metabolism, random migration and chemotaxis as well as elastase release. Elastase was chosen as a marker for primary granules. We observed inhibition of chemotaxis and random migration, and stimulation of oxidative metabolism as well as elastase release in presence of rh GM-CSF. These different effects were dependent on the dosage of rh GM-CSF applied.

Chemotaxis, Leukocyte↗
PubMed1988

[Proteases and their inhibitors in rapidly progressive and in juvenile periodontitis].

The purpose of this work was to study the elastase content of PMNs, the elastase alpha1-protease inhibitor complex, and the protease inhibitors in the plasma of patients with periodontal disease as compared with healthy subjects. We examined 11 patients with localized juvenile periodontitis (LJP), 15 patients with rapidly progressive periodontitis (RPP), and 22 healthy control subjects (HS). Our findings showed a significantly higher value for elastase like protease (ELP) complex in both patient groups than for the control group. In RPP patients, the ELP content of PMNs was below that in healthy subjects. Correlation between the ELP complex and the ELP content of PMN's was significantly positive. No such correlation could be discovered in the LJP group between the quantity of a1Pl and its inhibitory capacity, which may suggest a functional disorder involving the a1Pl of these patients. The imbalance existing between the different protease inhibitors is perhaps an explanation of the extensive tissue destruction occurring in periodontal disease as a result of the unrestrained effect of released granulocyte enzymes in the case of defective inhibition.

Adolescent↗
PubMed1988

Neutrophil function in patients with localized juvenile periodontitis and with rapidly progressive periodontitis.

PMN chemotactic function and oxydative metabolism were investigated in 13 patients with rapidly progressive periodontitis (RPP) and 9 patients with localized juvenile periodontitis (LJP) using a chemotaxis assay (CHA), luminol chemiluminescence (CL) and nitroblue-tetrazolium (NBT) tests. In the LJP patients there was a significantly lower CHA than in the RPP patients (less than 40%). Three out of the 13 RPP patients displayed a cell-dependent increase of CHA and in 3, the reduced CHA measured was serum-associated whilst among the 9 LJP patients, a cell-dependent defect of CHA was present in 5 patients, a serum-associated defect in one patient and a combined cell- and serum-associated defect was found in another patient. The average values of CL in the RPP patients were significantly lower (1309.3 +/- 814.2) than those measured in the LJP group (2208 +/- 826.9). In contrast, the mean NBT test values indicated a lower phagocytic function in the LJP patients than in the RPP ones suggesting also the presence of a serum-dependent factor in RPP and that of a combined cell- and serum-response in LJP. According to these results, the neutrophil dysfunction in RPP, as indicated by both the chemotaxis and the oxydative metabolism nature, was frequently associated with a serum factor.

Adolescent↗
PubMed1988

Modulation of functions of granulocytes by recombinant human GM-CSF and possible complications of GM-CSF therapy.

Besides its effect on bone marrow progenitors, GM-CSF is able to modulate functions of mature cells such as neutrophils. It inhibits random migration and chemotaxis through action on both cells and chemotactic factors, and stimulates oxidative metabolism as well as elastase release. Furthermore, it strongly enhances the response of the cells to the usual stimulants such as f-Met-Leu-Phe and phorbol esters. The role of neutral proteinases and activated oxygen species in different diseases such as ARDS, emphysema, coagulation defects, arthritis, and inflammation, is recognized. The remarkable in vitro release of neutral proteinases and activated oxygen species from granulocytes after GM-CSF stimulation may be of importance in vivo. This should be considered in clinical application of GM-CSF, particularly with high-dose therapy.

Cell Movement↗
PubMed1987

Amplification and expression of protooncogenes in human small cell lung cancer cell lines.

Amplification and expression of 16 protooncogenes were examined in 12 established small cell lung cancer (SCLC) cell lines. Seven of 12 cell lines showed a 20- to 35-fold amplification of the c-myc oncogene, 3 cell lines showed an 80- to 130-fold amplification of N-myc oncogene, and one cell line had a simultaneous amplification of the c-myb and N-myc oncogene. In this cell line both oncogenes were transcriptionally highly active at the same time. A variant subpopulation of SCLC expressed an 8.5-kilobase v-fms homologous transcript at high levels but without amplification of the c-fms gene. All cell lines examined had similar RNA levels of the N-ras, Ki-ras, Ha-ras, and c-raf1 oncogenes. DNA amplification, however, was undetectable. The protooncogenes c-fes, c-fos, and c-erbB were expressed very weakly and the transcripts of the oncogenes c-mos, c-sis, c-erbA, c-src, and c-abl were not observed in any of the 12 SCLC-cell lines. From these data we conclude that beyond the oncogenes myc and myb, oncogenes whose gene products are GTP binding proteins and phosphokinases may also be necessary to develop and keep the malignant state of SCLC. The v-fms homologous transcript found may be involved in the transition of the classic cell type to the variant cell type of SCLC.

Carcinoma, Small Cell↗