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Biomedical subjects

D Niethammer

Publications and source records attributed to D Niethammer.

At least 19 recordsLinked to original sources
PubMed1999

Acetyl-11-keto-beta-boswellic acid induces apoptosis in HL-60 and CCRF-CEM cells and inhibits topoisomerase I.

Antiproliferative action of different pentacyclic triterpenes has repeatedly been reported, and some lipoxygenase inhibitors have been shown to induce cell death in various cell systems. Acetyl-11-keto-beta-boswellic acid (AKBA) is a pentacyclic triterpene that inhibits 5-lipoxygenase in a selective, enzymedirected, nonredox, and noncompetitive manner. To investigate a possible effect of AKBA on leukemic cell growth, proliferation of HL-60 and CCRF-CEM cells was assayed in the presence of AKBA and a structural analog without effect on 5-lipoxygenase, amyrin. Cell counts and [3H]thymidine incorporation were significantly reduced in a dose-dependent manner in the presence of AKBA (IC50 = 30 microM) but not amyrin. An additive effect of AKBA with the crosslinking of the CD95 receptor was also observed. Flow cytometric analysis of propidium iodide-stained cells indicated that the cells underwent apoptosis. This was confirmed by flow cytometric detection of sub-G1 peaks in AKBA-treated cells and by DNA laddering. However, because HL-60 and CCRF-CEM do not express 5-lipoxygenase mRNA constitutively, a mechanism distinct from inhibition of 5-lipoxygenase must account for the effect of AKBA. In a DNA relaxation assay with phiX174RF DNA, AKBA inhibited topoisomerase I from calf thymus at concentrations of >/=10 microM. A semiquantitative cDNA polymerase chain reaction approach was used to estimate the relative level of expression of topoisomerases in both cell lines. The data suggest that induction of apoptosis in HL-60 and CCRF-CEM by AKBA may be due to inhibition of topoisomerase I in these cells.

Animals↗
PubMed1998

Rhodamine 123 efflux modulation in the presence of low or high serum from CD56+ hematopoietic cells or CD34+ leukemic blasts by B9309-068, a newly designed pyridine derivative.

The newly designed pyridine derivative B9309-068 and a series of structurally different compounds were tested for their ability to modulate rhodamine 123 (RHO) efflux from CD56+ hematopoietic cells in the presence of either 10% fetal calf serum or undiluted human AB serum. Furthermore, efflux modulation was investigated on CD34+ blast populations obtained from four patients with relapsed state AML. Target cells were specified throughout by labeling with peridinine chlorophyll protein (PerCP)-conjugated monoclonal antibodies, allowing clear differentiation from RHO emission spectrum by flow cytometry. In the presence of low serum each compound efficiently modulated RHO efflux without significant differences in the range of final concentrations (1.0-3.0 microM). At 0.1 microM, however, RHO efflux was differentially modulated following the series GF120918 approximately B9309-068 > PSC 833 > DNIG approximately DVER. With CD56+ cells in the presence of undiluted human AB serum at a final modulator concentration of 0.1 microM, all chemosensitizers tested were found to be inefficient. At final concentrations of 0.3 microM or higher, distinct RHO efflux modulation was found with the following efficacies: B9309-068 approximately GF120918 > PSC 833 >> DVER approximately DNIG. The efficacies seen in undiluted human AB serum at 3.0 microM were comparable to those seen on CD56+ cells at final modulator concentrations of 0.1 microM in low serum. Our results identify the pyridine derivative B9309-068 as a promising compound for modulating P-glycoprotein-mediated drug resistance under conditions resembling the clinical setting. Nonetheless, modulation potencies of a series of structurally very different chemosensitizers was revealed to be substantially diminished at high serum concentrations in vitro.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Ascorbic acid stimulates DOPA synthesis and tyrosine hydroxylase gene expression in the human neuroblastoma cell line SK-N-SH.

Ascorbic acid is well known to induce noradrenaline synthesis in sympathetic nervous cells. In a series of experiments we found that incubation of the neuroblastoma cell line SK-N-SH with ascorbic acid (100-500 microM) for 2 h results in a significantly enhanced synthesis of 3,4-dihydroxyphenylalanine (DOPA) and dopamine. Additionally, cDNA-polymerase chain reaction (cDNA-PCR) analysis of relative mRNA levels corresponding to the enzymes involved in catecholamine synthesis revealed a 3-fold increase of tyrosine hydroxylase gene expression after 5 days of incubation with ascorbic acid (200 microM), whereas expression of dopamine-beta-hydroxylase was found to be unaltered. In summary the data give evidence that ascorbic acid leads to enhanced DOPA production in SK-N-SH cells by two different mechanisms: at the metabolic level after short-term incubation and by increasing the tyrosine hydroxylase gene expression after long-term incubation. Based on these data we suppose that enhancement of DOPA synthesis by ascorbic acid may be useful in the treatment of early Parkinson's disease.

Ascorbic Acid↗
PubMed1998

Excess of mild errors of morphogenesis in childhood lymphoblastic leukemia.

The prevalence of 55 well-defined mild errors of morphogenesis (MEMs) was determined in 100 children with acute lymphoblastic leukemia (ALL), their 80 sibs, 91 mothers, and 76 fathers. Seventy-four patients were treated in Pécs (Hungary) and 26 in Tübingen (Germany). Only white Caucasian index cases were included in the study. Two-hundred children examined for acute infections served as controls. In addition, we analyzed the family history for birth defects and malignancies, associated major malformations, birth weight, birth order, and pretreatment height of the patients. The results of the Pécs and Tübingen patients were at first evaluated separately but since no differences were found only the cumulative data were analyzed further. A significantly increased prevalence of MEMs was found in the ALL patients and their sibs of both sexes: their MEM/subject ratios were 1.59 and 1.51, respectively, whereas the same parameter was 0.74 in the mothers, 0.67 in the fathers and 0.69 in the controls. The same tendency was observed when familial cases and/or age-dependent MEMs were excluded and when malformation-type and variant-type MEMs were evaluated separately. No association of ALL with specific MEMs or combinations was recorded. Family history, associated major malformations, parity and birth weight of the patients did not differ significantly from the local reference values, whereas the pretreatment height of the male probands proved to be greater than expected.

Adolescent↗
PubMed1998

Hepatic veno-occlusive disease in pediatric stem cell recipients: successful treatment with continuous infusion of prostaglandin E1 and low-dose heparin.

Limited data exist on therapeutic options for established hepatic veno-occlusive disease (VOD) in pediatric patients after stem cell transplantation (SCT). In this report, we present data on the successful treatment of VOD in three children following allogeneic SCT and report the duplex ultrasound criteria for the confirmation of the diagnosis and for the evaluation of the treatment progress. All patients were <2 years at the time of transplantation and had received preparative regimens containing busulfan and cyclophosphamide. There were no known pretransplant risk factors for VOD. Allogeneic stem cell transplantation was performed from a sibling donor for CMML and from unrelated donors for Wiskott-Aldrich syndrome and familial hemophagocytic lymphohistiocytosis (FHL). The onset of first clinical symptoms of VOD (as defined by the Seattle and Baltimore criteria) was relatively late in all three patients (days +19, +20, and +25, respectively). Time from onset of first symptoms until confirmation of diagnosis by serial duplex ultrasound examination was 4-11 days. Duplex ultrasound criteria are as follows: complete change of direction of blood flow in the portal vein, decrease of flow in the hepatic veins, and development of collateral circulation. Treatment was initiated upon confirmation of VOD by continuous infusion of prostaglandin E1 (initial dose 0.075 microg/kg/h) in addition to low-dose heparin (100 units/kg/d). Treatment was continued at the maximum tolerated dose of 0.3-0.5 microg/kg/h of PGE1. After 9, 14, and 25 days of treatment respectively, normal portal vein flow was restored and treatment could be discontinued. All three patients are alive and well without apparent sequelae.

Alprostadil↗
PubMed1998

Phenotypic and functional characterization of mobilized peripheral blood CD34+ cells coexpressing different levels of c-Kit.

In this report we evaluated the exact expression pattern of c-Kit on mobilized peripheral blood (PB) CD34+ cells. Using a monoclonal antibody against CD117 antigen (95C3), flow cytometric analysis revealed that approximately 25% of the mobilized PB CD34+ cells coexpress c-Kit. This cell fraction showed a considerable heterogeneity with respect to c-Kit expression, consisting of a small fraction with high levels of c-Kit (4.2%) (CD34+/CD117high fraction) and a larger proportion of cells expressing low levels of this antigen (21.0%) (CD34+/CD117low fraction). Clonogenic assays showed that CD34+/CD117high cell fraction consisted almost exclusively of erythroid progenitors, in contrast to CD34+/CD117low cell subset which gave rise mostly to granulocyte-monocyte colonies. The majority of CFU-GEMM and the most primitive week 6 cobblestone area forming cells (CAFCs) segregated in the CD34+/CD117low cell subset, suggesting the highest content of multipotential progenitors within this cell fraction. None of the sorted cell subsets was able to produce reactive oxygen intermediates (ROI). However, ex vivo expansion of the sorted subsets with interleukin 3, stem cell factor and FLT3 ligand for 2 weeks resulted in a significant production of O2- and H2O2/HOCl by CD34+/CD117low cell fraction, compared to the same sorted but not expanded counterparts. According to the major content of multipotential hematopoietic progenitors and highest capacity to generate sufficient amounts of ROI after ex vivo expansion, we suggest that CD34+/CD117low cell subset would be one of the most potential candidates for transplantation in patients with acute lymphoblastic leukemia, which lack c-Kit antigen expression.

Antigens, CD34↗
PubMed1998

Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy. A pilot study.

Disseminated neuroblastoma after infancy has a prognosis of approximately 10-20% with conventional therapy. We investigated the role of high-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) rescue in combination with 131I-metaiodobenzylguanidine ([131I-m]IBG). 11 children with neuroblastoma stage 4 were pretreated within the German Neuroblastoma Trial NB90 and included in a high-dose concept for consolidation. Remission was documented by ultrasound, CT, NMR, or [123I-m]IBG scanning. HDCT was a combination of melphalan (180 mg/m2), carboplatin (1,500 mg/m2) and etoposide (40 mg/kg). All children were treated by [131I-m]IBG (0.58 GBq/kg) prior to high-dose treatment. All 11 children were additionally treated with antiGD2 murine- or chimeric-antibody (ch14.18). 4 children had no change to their remission status but three achieved a complete response (from a partial response to first line) and one a partial response (from no response to first line). The other 3 children progressed, 2 dying of their disease. Using Kaplan-Meier analysis, the probability of progression-free survival was 0.70 +/- 0.15 with a median observation time of 19 months. 9/11 children are alive, 8 without progression or relapse, whilst 2 have died of their disease. The combination of mIBG plus high-dose chemotherapy with PBSC support supplemented by immunotherapy with antiGD2 antibody appears to be a feasible and effective treatment regimen for disseminated neuroblastoma in this limited series. Larger numbers of patients should be treated to confirm these results.

3-Iodobenzylguanidine↗
PubMed1998

Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlations of PKC eta with MDR1, MRP and LRP gene expression.

A possible link between protein kinase C (PKC) and P-glycoprotein (P-gp)-mediated-multidrug resistance (MDR) was assumed from studies on MDR cell lines selected in vitro. The functional relevance of PKC for the MDR phenotype remains unclear, and the involvement of a particular PKC isozyme in clinically occurring drug resistance is not known. Recently, we have demonstrated significant correlations between the expression levels of the PKC eta isozyme and the MDR1 or MRP (multidrug resistance-associated protein) genes in blasts from patients with acute myelogenous leukaemia (AML) and in ascites cell aspirates from ovarian cancer patients. To extend these findings to further types of human tumours we analysed specimens from 64 patients with primary breast cancer for their individual expression levels of several MDR-associated genes (MDR1, MRP, LRP (lung cancer resistance-related protein), topoisomerase (Topo) II alpha/IIbeta, cyclin A and the PKC isozyme genes (alpha, beta1, beta2, eta, theta, and mu) by a cDNA-PCR approach. We found significantly enhanced mean values for MRP, LRP and PKC eta gene expression, but significantly decreased Topo II alpha and cyclin A gene expression levels in G2 tumours compared with G3. Remarkably, significant positive correlations between the MDR1, MRP or LRP gene expression levels and PKC eta were determined: MDR1/PKC eta (rs = +0.6451, P < 0.0001) n = 62; MRP/PKC eta (rs = +0.5454, P < 0.0001) n = 63; LRP/PKC eta (rs = +0.5436, P < 0.0001) n = 62; MRP/LRP (rs = +0.7703, P < 0.0001) and n = 62, MDR1/MRP (rs = +0.5042, P < 0.0001) n = 62. Our findings point to the occurrence of a multifactorial MDR in the clinics and to PKC eta as a possible key regulatory factor for up-regulation of a series of MDR-associated genes in different types of tumours.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe in 1998. Accreditation Sub-Committee of the European Group for Blood and Marrow Transplantation.

In 1996, the Accreditation Sub-Committee of the EBMT published a special report summarising current practice in Europe in relation to haemopoietic stem cell transplants for haematological diseases, solid tumours and immune disorders. An updated report is presented here. The major change has been the recognition that transplant practice is appreciably different between children and adults, who should therefore be considered in separate categories. The autoimmune disorders for which autografting may be useful are now specified. Non-CML myeloproliferative disorders and AL amyloidosis have been added to the list of indications for transplant procedures in adults. Other changes have been incorporated into the revised tables.

Adolescent↗
PubMed1998

Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT.

Within a prospective study we analyzed hematopoietic chimerism in serial peripheral blood samples taken from 55 patients with acute leukemias (ALL 21, AML 20, MDS 14) with a median age of 13.5 years at very short time intervals following allogeneic bone marrow transplantation (allo-BMT). The investigation was performed to determine the implications of mixed hematopoietic chimerism (MC) with regard to the clinical outcome in patients with acute leukemias after allo-BMT. Analysis of chimerism was performed by PCR of variable number of tandem repeat (VNTR) sequences with a maximum sensitivity of 0.8%. Thirteen male patients transplanted with the marrow of a female donor were also studied by amplification of a Y-chromosome-specific alphoid repeat (0.1-0.01% sensitivity). VNTR analysis in 55 patients revealed complete chimerism (CC) in 36 cases, MC in 18 follow-ups and autologous recovery in one patient. Quantitative analysis of MC identified 10/18 patients with increasing autologous patterns in whom 9/10 subsequently relapsed. The patient with autologous recovery relapsed as well. Eight of 18 patients with MC showed decreasing amounts of autologous DNA and became CC upon further follow-up. In contrast, only 7/36 patients with CC in the prior analysis of chimerism status relapsed. However, in 4/7 patients the interval between last CC confirmation and relapse was more than 4 months. In 2/7 patients autologous DNA was not detectable in peripheral blood but in bone marrow aspirates. One of these seven patients developed a fulminant relapse within 3 weeks. The probability of relapse-free survival for patients with CC is 0.67 (n = 36), for patients with decreasing MC 1.0 (n = 8) and for patients with increasing MC 0.1 (n = 10). In summary, the results demonstrate that serial and quantitative chimerism analysis at short time intervals by PCR provides a reliable and rapid screening method for the early detection of recurrence of underlying disease and is therefore a prognostic tool to identify patients at highest risk of relapse.

Acute Disease↗
PubMed1998

Isolation and transplantation of autologous peripheral CD34+ progenitor cells highly purified by magnetic-activated cell sorting.

Peripheral stem cells were mobilized and collected in 26 pediatric patients with malignant diseases. A total of 47 leukaphereses were performed in the 26 patients. The mean number of nucleated cells collected was 4.5 +/- 2.6 x 10(8)/kg and the number of CD34+ progenitors collected was 6.7 +/- 6.8 x 10(6)/kg. CD34-positive selection was performed using a two-step method of magnetic-activated cell sorting (MACS) in 24 patients or a combination of an immunoaffinity column and MACS in two patients. The purity of the positively selected CD34+ progenitors was 98.8 +/- 0.7% and the number of isolated CD34+ cells was 6.5 +/- 5.9 x 10(6)/kg. Thus, the mean recovery of CD34+ cells was 93 +/- 10%. In 22 of the 26 patients, high-dose chemotherapy was performed with subsequent reinfusion of the highly purified CD34+ cells. In all 22 patients, a normal hematopoietic reconstitution was seen with a mean time of 12.4 +/- 2.7 days to reach >0.5 x 10(9)/l neutrophils (range 8-19 days). The time to reach independence from platelet transfusion was 31.6 +/- 17.0 days (range 16-78 days). There were no transplant-related deaths. In summary, we have shown that mobilized peripheral CD34+ progenitors can be highly purified with a good recovery, and that reinfusion of these cells after high-dose chemotherapy results in a rapid, complete and sustained engraftment. We conclude that this method can be used for purging in any CD34-negative malignancies and for autologous T and B cell depletion in the treatment of autoimmune diseases with high-dose immunoablative therapy.

Adolescent↗
PubMed1998

Transplantation activities and treatment strategies in paediatric stem cell transplantation centres: a report from the EBMT Working Party on Paediatric Diseases. European Group for Blood and Marrow Transplantation.

To determine the current approach to stem cell transplantation (SCT) in centres which treat predominantly paediatric patients, a questionnaire was sent to 67 centres known by the EBMT registry to perform SCT mainly in children. Fifty-five centres from 19 countries responded. Forty centres (75%) started their transplantation activities between 1980 and 1992. Median number of transplants/centre was 95 (range 8-400). Median number of transplants/centre/year was 18 (range 5-85). On average, there was one physician responsible for seven SCT/year while one nurse was involved for a median of 1.7 SCT/year. Median four rooms/centre (range 1-17) were available for paediatric SCT. The most common isolation facilities were rooms with high efficiency particulate air filtration (HEPA). Eighty-two percent (45/55) of the centres performed allogeneic as well as autologous SCT, while 5% (three centres) offered exclusively allogeneic SCT and 13% (seven centres) used only autologous stem cell rescue. Stem cell source for allogeneic SCT was bone marrow in 87%, peripheral blood (PB) in 10% and umbilical cord blood in 3%. Donors were HLA matched related in 57%, mismatched related in 13%, and matched unrelated in 30% of allogeneic SCT. PB was the most commonly used stem cell source for autologous SCT (48%), followed by BM (41%) and the two together (11%). Data analysis revealed substantial differences in protective care, stem cell processing and transplantation procedures within the centres, irrespective of the country, centre size and transplant type.

Adolescent↗
PubMed1998

Activation-dependent expression of the insulin-like growth factor binding protein-2 in human lymphocytes.

The expression of the insulin-like growth factor binding protein-2 (IGFBP-2) was assayed in mononuclear cells originating from different organs of the immune system. All mononuclear cells studied did express IGFBP-2, but the expression level was found to be dependent on the cell type and origin of the cell. T cells showed a higher expression of IGFBP-2 mRNA than did B cells, and CD34+ stem cells expressed IGFBP-2 mRNA at a high level. Expression was highest in bone marrow and thymus. Stimulation of peripheral mononuclear cells resulted in a marked increase of IGFBP-2 mRNA and also intracellular IGFBP-2, as analysed by fluorescence staining. This increase parallels the increase of other known T-cell activation markers. Furthermore, the increase of intracellular IGFBP-2 seems to precede T-cell blast formation and all T cells in active phases of the cell cycle have high levels of IGFBP-2. Our results provide a basis for further investigations on the contribution of the IGF-system to the regulation of T-cell proliferation and differentiation. IGFBP-2, in particular, may have an important influence in the regulation of T-cell activation and proliferation.

Cell Culture Techniques↗
PubMed1998

Elevated major histocompatibility complex class I expression protects T cells from antibody- and macrophage-mediated deletion.

Macrophages are capable of destroying T cells with which they form cellular conjugates. The deletion can be prevented by the simultaneous transmission of costimulatory signals. We show here that T cells with elevated major histocompatibility complex (MHC) class I expression are resistant against macrophage-mediated cytotoxicity. T cells that express the CD45RO isotype, considered memory T cells, exhibit MHC class I antigen at higher density than naive CD45RA T cells and upregulate MHC class I expression promptly when they form cellular conjugates with macrophages. We confirm previous observations that CD45RA T cells are more susceptible to antibody- and macrophage-mediated deletion than memory CD45RO T cells. When MHC class I molecules are masked by specific monoclonal antibody or antibody Fab fragments, CD45RA T cells and CD45RO T cells exhibit equal susceptibility to macrophage cytotoxicity, demonstrating that the difference between CD45RA and CD45RO T cells in their sensitivity to macrophage cytotoxicity is determined by their MHC I expression. Separation of CD4 T cells from CD8 T cells deprives memory CD4 T cells of their resistance against macrophage cytotoxicity, suggesting that memory T cells' resistance against destruction by macrophages is controlled by regulatory T cells.

Antibodies, Monoclonal↗
PubMed1998

Anthracycline-derived chemotherapeutics in apoptosis and free radical cytotoxicity (Review).

Anthracycline-derivatives are frequently used chemotherapeutics in treatment of numerous human malignancies. Anthracyclines are known for their complex cytotoxic mechanism involving i) inhibition of enzymes such as topoisomerase II, RNA polymerase, cytochrome c oxidase and others; ii) intercalation into DNA; iii) chelation of iron and generation of reactive oxygen species (ROS); iv) induction of apoptosis. Here, mechanistic aspects for successful cytostasis and for side effects, e.g. cardiomyopathy, are discussed. We emphasize recent developments in anthracycline-mediated apoptosis and focus on a well known representative, doxorubicin (adriamycin, adriblastin). We reflect on the role of oxidative stress and interactions with intracellular signaling pathways.

Animals↗
PubMed1998

Proposal for standard recommendations for prophylaxis of graft-versus-host disease in children. European Group for Blood and Marrow Transplantation (EBMT) Working Party Paediatric Diseases and the International Study Committee of the BFM family-subcommittee Bone Marrow Transplantation (IBFM-STG).

Great variations exist in the practices of graft-versus-host disease prophylaxis for children undergoing allogeneic stem cell transplantation. It was the aim of the EBMT Working Party on Paediatric Diseases and the International Study Group of the BFM-Family, subcommittee bone marrow transplantation (IBFM-SG) to define standard recommendation for prevention of GVHD. Thus a survey was carried out among the local representatives of the EBMT WP and IBFM-SG members to define standards for GVHD prophylaxis basing on available literature data, discussion with colleagues and their own experience. Presently the majority of regimen for GVHD prophylaxis are centred on CsA and a short course of MTX with addition of some other immunosuppression (eg ATG or ALG) in patients with high risk for severe GVHD. The proposal defined different category of patients: patients with malignant disease who are either transplanted from HLA matched sibling donors or HLA mismatched family donors (or volunteer unrelated donors) and patients with non malignant disease who might not benefit from graft-versus-leukaemia effect having either an HLA matched sibling donor or an HLA mismatched family donor (or volunteer unrelated donor). Homogeneous GVHD prophylaxis for defined patient groups should provide better information to optimise strategies in reducing treatment related toxicity and incidence of relapse by increasing GVL effect.

Adolescent↗
PubMed1998

Long-term survivors: an overview on late effects, sequelae and second neoplasias.

A large number of haematological and oncological diseases as well as inborn errors can be cured today by stem cell transplantation. However, the chemotherapy and radiation used for the preparation of BMT can induce late effects which can be rather severe. Especially in malignant diseases the late toxicity of previous conventional therapy has an additional impact. The function of various organs can be impaired, such as the eyes, the central nervous system, the teeth, the legs, the heart, the kidneys, the liver, the endocrine functions and growth. Second neoplasias occur during various times after BMT: lymphoproliferative disease may occur during the first year, leukemias and myelodysplastic syndromes develop after several years, whereas solid tumours occur even later. The incidence of second neoplasias after BMT seems to be higher in children than in adults. Many late sequelae as well as psychological disturbances can impair the quality of life of the survivors of BMT. Paediatricians should take this fact into account when they think about stem cell transplantation in a child. This all means that a long-term observation in these persons is necessary and this is done best within a standardised follow-up programme. Meanwhile such programmes have been developed in some countries, and this should be promoted within the working party 'Paediatric Diseases' of EBMT.

Bone Marrow Transplantation↗