-
Ž . JOURNAL OF MATHEMATICAL ANALYSIS AND APPLICATIONS. ; 218.
-
[show abstract]
[hide abstract]
ABSTRACT: German physicians are obligated (Para 16e Chemicals Law) to submit essential data on poisonings to the Centre for Documentation and Assessment of Poisonings at the Federal Institute for Risk Assessment (Bundesinstituts für Risikobewertung, BfR). In addition, German poison centres are subjected to compulsory reporting of their findings of general importance gained in the context of their activities. The BfR assessment of poisonings has important significance for human case data collection, risk identification, and German toxicological monitoring. Using more than 60,000 reports on cases of poisoning, the BfR developed a structured expert judgement trial for poisonings. This judgement is based on a three-level model, accompanied by two different matrix procedures for an enhanced and more exact assessment of the exposures and the causality between health impairment and exposure. Particularly for low-dose exposures, human biomonitoring data is extremely valuable for the assessment process. Especially in chronic low-dose level exposures, the scientific assessment of related health impairments is often not possible without existing human biomonitoring data. For the future improvement of public health related to poisonings, ingestions by children, workplace chemical exposures, and incidents, we have to establish a nation-wide programme for monitoring human exposures which keeps pace with the progressive production of new chemicals. This must be done in close co-operation with physicians, poison centres, government safety organisations, and environmental health specialists and must be based on proven expert judgement tools and available human biomonitoring data.
International journal of hygiene and environmental health 02/2012; 215(2):242-6. · 2.64 Impact Factor
-
Journal of neurological surgery. Part A, Central European neurosurgery. 01/2012;
-
[show abstract]
[hide abstract]
ABSTRACT: The bone marrow micro-environment produces a number of different survival factors that are important for the malignant growth and drug resistance of multiple myeloma (MM) cells. One of the main factors reported to be essential for survival and growth of MM cells in some experimental systems is IL-6. Therefore, the development and testing of substances that interfere with IL-6 or IL-6 receptor (IL-6R) function might have therapeutic value for the treatment of MM. We analyzed the effect of the IL-6R antagonist SANT-7 on growth and survival of the IL-6--dependent MM cell lines INA-6 and XG-1 as well as primary MM cells from 7 patients co-cultured with bone marrow stromal cells (BMSCs). In particular, we were interested in whether SANT-7 enhances the growth-inhibitory effects of dexamethasone (Dex) and all-trans-retinoic acid (ATRA). None of the drugs when tested as a single substance, including SANT-7, induced major growth inhibition if MM cells were co-cultured with primary human BMSCs. However, when Dex and ATRA were given in combination with SANT-7, strong growth inhibition was achieved in cell lines and primary MM cells. This effect was due to cell-cycle arrest and induction of apoptosis.
International Journal of Cancer 10/2001; 93(5):674-80. · 5.44 Impact Factor
-
R Burger,
A Guenther,
F Bakker,
M Schmalzing,
S Bernand,
W Baum,
B Duerr,
G M Hocke,
H Steininger,
E Gebhart,
M Gramatzki
[show abstract]
[hide abstract]
ABSTRACT: Cytokines of the gp130-family, particularly interleukin(IL)-6, play a crucial role in the propagation of malignant plasma cells.
The role of IL-6 and other gp130-cytokines was studied in the human plasma cell line INA-6 in vitro and in INA-6 xenografts. The proliferative response to gp130-cytokines was evaluated and activated components of gp130-signaling pathways were identified by Western blotting and DNA binding studies. Specifically, expression of IL-6 and receptors for IL-6 and leukemia inhibitory factor were analysed by RT-PCR and ELISA.
The plasma cell line INA-6 was cultured for several years remaining strictly dependent on exogenous IL-6. Other gp130-cytokines had no significant effect on INA-6 cell proliferation in vitro. Due to an activating mutation in the N-ras gene, mitogen-activated protein kinases (MAPK) were constitutively phosphorylated. In contrast, signal transducer and activator of transcription(STAT)-3 activation was dependent on stimulation with IL-6. Blocking of either one of these pathways resulted in a significant decrease of INA-6 cell proliferation. Remarkably, INA-6 xenografts did not require exogeneous IL-6 for proliferation in vivo. Instead, an autocrine IL-6 loop and, in certain tumor sublines, responsiveness to additional gp130-cytokines was induced during in vivo growth.
Activation of the gp130 signal transducer is mandatory for INA-6 cell growth in vitro and in vivo. Both the MAPK and the Jak/STAT pathway are operative in malignant plasma cells and either one is essential for plasma cell growth. The INA-6 cell line provides a preclinical model to study growth regulation of human plasmacytoma cells and to evaluate novel therapeutic strategies.
The Hematology Journal 02/2001; 2(1):42-53. · 1.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We present a complete solution of the batch sedimentation process of an initially homogeneous ideal suspension where the Kynch batch flux density function is allowed to have two inflection points. These inflection points can be located in such a way that during the sedimentation process, the bulk suspension is separated from the supernate by a rarefaction wave or concentration gradient. This observation gives rise to two new modes of sedimentation as qualitative solutions of the batch sedimentation problem that had not been considered in previous studies. A reanalysis of published experimental data indicates that several observed upper concentration gradients can actually be interpreted as a rarefaction wave, and therefore be included in the framework of Kynch's theory. A numerical example shows an upper rarefaction wave in the settling of a flocculated suspension, to which Kynch's theory applies if the solid particles are in hindered settling. q 2000 Elsevier Science S.A. All rights reserved.
Ž . Powder Technology. 01/2000; 108:74-87.
-
[show abstract]
[hide abstract]
ABSTRACT: Hematopoietic cell lines are often used as representatives for a certain cell differentiation lineage and stage, particularly in immunological and hematological studies. Acute lymphoblastic leukemia (ALL) of T-cell type is a rather heterogeneous group of ALL at least by immunophenotyping. Our aim was to present a comprehensive characterization of frequently used T-cell leukemia cell lines and to suggest a correlation with the normal differentiation pattern. A total of 16 T-ALL cell lines were analyzed for their immunophenotype and for T-cell receptor (TCR) rearrangement and expression. The panel of 20 cell surface markers included two new monoclonal antibodies (MoAb), TC-12 and TH-111, which were raised in our laboratory and detect subpopulations of T-cell ALL. TC-12 was typed 'unique', TH-111 was assigned to the CD96 cluster at the Vth Conference on human leucocyte differentiation antigens (HLDA). We categorized the 16 cell lines into the four groups pro-T, pre-T, cortical T and mature T differentiation stage according to the recent proposal of the European Group for the Immunological Characterization of Leukemias (EGIL). Interestingly, none of the T-cell lines were found to be alike. In conclusion, it appears necessary to consider the particular differentiation stage of each individual cell line when using T-cell leukemia lines as models for malignant or normal T cells.
Leukemia Research 02/1999; 23(1):19-27. · 2.92 Impact Factor
-
M Gramatzki,
W D Ludwig, R Burger,
P Moos,
P Rohwer,
C Grünert,
A Sendler,
J R Kalden,
R Andreesen,
F Henschke,
G Moldenhauer
[show abstract]
[hide abstract]
ABSTRACT: To extend the panel of monoclonal antibodies useful for immunophenotyping of acute leukemias, two new reagents, TC-12 and TH-111, were developed. TC-12 was found "unique," and TH-111 was assigned to the recently defined CD96 cluster. Both reagents show little reactivity with blood and bone marrow nucleated cells but define a major (TH-111: 78.3%) or an important (TC-12: 45.6%) subset of T-cell acute lymphoblastic leukemia (ALL). In addition, in acute myeloid leukemia (AML), the expression of TC-12 was found in 64 (20.2%) of 317 and TH-111 in 97 (29.1%) of 333 of these patients. TC-12 positivity in AML was virtually restricted to the Fab subtypes M0, M1, M2, and M6. In the group of immature AML characterized by the coexpression of CD7 as well as CD117 and CD34 positivity, leukemic blasts frequently disclosed the TC-12 and TH-111 antigen. Although the TC-12 antigen could not be determined, TH-111 immunoprecipitated the TACTILE (CD96) antigen and, when expressed, was found to be associated with the transferrin receptor. These reagents may help not only to define and dissect T-cell ALL, but also to characterize a subgroup of immature AML at the divergence of T-cell and myeloid lineage.
Experimental Hematology 01/1999; 26(13):1209-14. · 2.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Differentiation of the myeloid leukemia cell line M1 by treatment with IL6-type cytokines depends on activation of the Jak/Stat (Janus kinase/signal transducer and activator of transcription) pathway. Defects in this cascade are correlated with an impaired cytokine-inducible differentiation of various other myeloid cell lines. Although treatment with IL-6 increased the amount of activated transcription factor Stat3 in the myeloid leukemia line C, differentiation was not induced. However, after cotransfection with expression constructs for the tyrosine kinase Jak2 and Stat factors 3 or 5a, treatment of the cells with IL-6 caused a decrease in the number of viable cells. In parallel, an increase in the percentage of differentiated cells occurred. These findings are consistent with the hypothesis that the Jak/Stat signaling cascade plays an important role in cytokine-induced differentiation of myeloid leukemia cells.
Biochemical and Biophysical Research Communications 10/1998; 250(2):436-43. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Seroepidemiology and polymerase chain reaction studies have strongly suggested that human herpesvirus type 8 (HHV-8) is associated with Kaposi's sarcoma, Castleman's disease, and body cavity-based lymphoma. The genome of HHV-8 harbors a viral analogue of the interleukin-6 (IL-6) gene. The amino acid sequence of the viral IL-6 (vIL-6) protein is 24.7% identical to human IL-6 (hIL-6). IL-6 as a B-cell growth and differentiation factor is known to play an essential role in the pathophysiology of B-cell tumors. Thus, it seems possible that virus-encoded IL-6 contributes to malignant growth of HHV-8-positive B-cell lymphatic tumors. We have tested a preparation of HHV-8-derived IL-6 for the ability to promote the proliferation of the human myeloma cell line INA-6, which is strictly dependent on exogenous IL-6 for growth and survival. Viral IL-6 significantly induced DNA synthesis of INA-6 cells, but required much more protein on a weight basis when compared with hIL-6 for maximal proliferation. The proliferative effect of vIL-6 was almost completely inhibited by a combination of anti-IL-6 receptor (IL-6R) and anti-gp130 antibodies or IL-6R superantagonist Sant7 and anti-gp130 antibodies. This report demonstrates that vIL-6 has proliferative activity on human cells and that the IL-6R and gp130 are involved in vIL-6 signaling in the myeloma cell line INA-6.
Blood 04/1998; 91(6):1858-63. · 9.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Administration of cytokines to patients with leukemia or lymphoma may recruit dormant malignant cells into cell cycle and thus make them more susceptible to chemotherapy. We treated a patient with refractory T cell acute lymphoblastic leukemia (ALL) with OKT3 monoclonal antibody and observed a dramatic but transient decrease of lymphoblasts. The T ALL cells were rather mature by morphology and immunophenotyping, expressing CD7, CD4, CD8 and CD3 surface antigens and nuclear TdT. Cytogenetic analysis revealed inversion of chromosome 14(q11q32.1). A total of 500 mg OKT3 (maximum dose 50 mg/day) was given. A decrease of lymphoblasts in the blood and a reduction of spleen size was observed. Complement levels dropped remarkably. Despite increasing serum levels of tumor necrosis factor, treatment was well tolerated overall. CD3 therapy induced strong IL-2 responsiveness of the lymphoblasts. Thus, OKT3 antibody treatment not only significantly decreased CD3-positive tumor cells, but also induced IL-2-mediated proliferation. This may also allow sequential application of CD3 and IL-2 to render certain T cell tumors more susceptible to chemotherapy.
Leukemia 04/1995; 9(3):382-90. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Functioning as a B-cell growth and differentiation factor, interleukin-6 (IL-6) may play an important role in the pathophysiology of B-cell tumors. The capacity for IL-6 secretion was evaluated in 58 patients with various B-cell leukemias/lymphomas and in four patients with Castleman's disease (CMD). Cell populations from various sites including peripheral blood, bone marrow, lymph nodes, and osteolytic bone lesions were cultured and tested for spontaneous or IL-1 beta/TNF alpha-induced IL-6 production in a sensitive bioassay. No significant IL-6 levels were released by the tumor cells in any of the B-cell leukemias or lymphomas tested, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (B-CLL). In contrast, purified malignant plasma cells were found to secrete IL-6, strengthening the idea that an autocrine pathway for growth regulation in multiple myeloma (MM) exists. For the first time, in several patients with CMD, peripheral blood cells were shown to produce extremely high levels of IL-6, the pathogenetic significance of which remains to be elucidated. However, similar observations were very occasionally made in MM patients. Therapy with corticosteroids strongly inhibited this IL-6 production. These data provide evidence for autocrine and possibly an additional paracrine regulatory loop in plasma cell neoplasias and CMD.
Annals of Hematology 08/1994; 69(1):25-31. · 2.62 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A cell line, designated SEM, was established from the peripheral blood of a 5-year-old girl in relapse with acute lymphoblastic leukaemia (ALL). Both the lymphoblasts of the patient and the cells of the cell line SEM showed the t(4;11) chromosomal rearrangement. The analysis of the immunophenotype of the SEM cell line revealed the B-cell differentiation antigens CD19, CD22 and CDw75 in the absence of CD20, CD24 and immunoglobulin expression. Besides B-lineage antigens, SEM cells were positive for the myeloid antigens CD13, CD15, CD33 and CDw65. Immunogenotypic analysis of SEM cells showed a monoclonal rearrangement of immunoglobulin heavy-chain (IgH). T-cell receptor (TCR) gamma and delta genes. Addition of interleukin (IL)-7 promoted the growth of the patient's lymphoblasts in culture and enhanced the proliferation of SEM cells. The SEM cells also express messenger RNA (mRNA) for the IL-7 receptor (IL-7R), but no evidence for autocrine production of IL-7 by the cell line was found. Addition of IL-4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-alpha, or IFN-gamma resulted in a profound inhibition of SEM growth. Thus, these cytokines may have important growth regulatory activities for biphenotypic leukaemic ALL cells.
British Journal of Haematology 03/1994; 86(2):275-83. · 4.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mononuclear cells from peripheral blood and bone marrow from patients with chronic lymphocytic leukemia (CLL) were cultured with interleukin-4 (IL-4) alone or with IL-4 and hydrocortisone (HC) in order to induce IgE synthesis. From a total of 29 experiments with the cells of 17 different donors an IgE secretion was observed only twice. Even in those two cases the IgE was found to be not monoclonal. The additional stimulation of CLL cells by polyclonal B cell activators induced IgM but not IgE production. When CLL cells were cocultured with monocyte-enriched cell preparations (M phi) in the presence of IL-4 and HC, a substantial IgE secretion could be obtained, which again consisted of both IgE kappa and IgE lambda. Since the irradiation of the M phi but not of the CLL cells abolished the formation of IgE, it is likely that the IgE production resided in the contaminating B cell population of the M phi. When the M phi were replaced by T cell-depleted peripheral blood mononuclear cells (non-T cells), irradiated as well as formaldehyde fixed CLL cells were able to stimulate non-T cells to secrete IgE in the presence of IL-4 or to potentiate IL-4- and HC-induced IgE formation. Furthermore, the coculture of irradiated pure CLL cells and purified B cells induced not only IgE but also IgG and IgM production and B cell proliferation in the presence of lymphokines. Our findings suggest that CLL cells, contrary to current opinion, cannot be induced to produce IgE.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Clinical Immunology 12/1993; 13(6):397-405. · 3.08 Impact Factor
-
Journal of Immunological Methods 02/1993; 158(1):147-8. · 2.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Two new monoclonal antibodies, EBU-65 and EBU-141, were raised by immunization with plasma cell line U-266. Both antibodies strongly react with B lymphocytes in immunofluorescent staining as well as on paraffin-embedded sections. More than 200 leukemias and lymphomas were tested, and for both antibodies reactivity was found only with "mature" B-cell tumors but not with precursor B-cell leukemias. None of the non-B-lineage hematolymphatic tumors tested was stained by EBU-141 or EBU-65. A subpopulation of T lymphocytes particularly present in nonmalignant pleural effusions was detected by EBU-65 additionally. Although EBU-141 was clustered as CDw75 and EBU-65 as "unique," a close relationship of the staining pattern was found and both antibodies react with a sialyltransferase. In particular, CDw75 antibody EBU-141 was demonstrated to be very useful for immunophenotyping of B-cell neoplasias, while EBU-65 reacted with most multiple myelomas and a subgroup of "activated"-appearing T cells.
Annals of Hematology 08/1991; 63(1):20-6. · 2.62 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mycoplasma can be removed from the surface of contaminated human and murine cell lines by incubation for 4 h with human, rabbit, guinea pig, or mouse sera. Several lines of evidence suggest the involvement of complement in this process: (1) The activity can be abrogated by heat treatment (56 °C for 45 min). (2) Using monoclonal antibodies directed against C3a and C3b, the deposition of C3b fragments on the surface of mycoplasmapositive cells can be demonstrated after 1 h incubation with human serum. (3) Ca2+ depletion ablates the ability of serum to remove the activity. (4) C2def′ sera are inactive while addition of purified C2 reconstitutes the activity. The latter two findings implicate that activation of the classical pathway of complement is responsible for the effect. Antibody, however, is not required as demonstrated by the uncompromised activity of Igdeficient sera from bursectomized chicken. Treatment with human serum or rabbit serum was used successfully to permanently cleanse tumor cell lines of human and of murine origin. The complete removal of mycoplasma was monitored over at least 8 weeks by direct DNA staining and confirmed by agar culture and transfer of supernatants to mycoplasma-free Vero cells followed by DNA staining. Thus the direct interaction of mycoplasma and complement appears to be an effective and rapid means of curing cell lines from mycoplasma.
Experimental Cell Research.
-
I Strohscheer,
R Kleinert,
C. Westphal,
J Schüller,
K. Werner,
O Anders,
H Wandt,
U. Poppy,
K Matthes,
M Kuliszkiewicz-Janus, [......],
G Schneider,
D. M. Rozynkowa,
H Kasparu,
G Gastl,
N Schwella,
H Wachter,
K Gabryś,
S Kleiner,
D Jakschies,
J Krauter
