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E Koller

Publications and source records attributed to E Koller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Human platelets exclusively bind oxidized low density lipoprotein showing no specificity for acetylated low density lipoprotein.

The widely studied macrophage scavenger receptor system is known to bind both acetylated low density lipoprotein and oxidized low density lipoprotein. Although only the latter ligand has been shown to occur in vivo, acetylated low density lipoprotein is often used to evaluate the contribution of scavenger receptors to different (patho)physiologic processes, assuming that all existing subtypes of scavenger receptors recognise both lipoproteins. In the present work, we identify human platelets as the first natural cell type to bind oxidized low density lipoprotein without showing specificity for acetylated low density lipoprotein. Consequently, platelets possess exclusive receptor(s) for oxidized low density lipoprotein distinct from the 'classical' scavenger receptor AI/AII. From the data presented in this work, we conclude that the class B scavenger receptor CD36 (GPIV) is responsible for this exclusive oxidized low density lipoprotein binding.

Animals↗
PubMed1999

Platelet high affinity low density lipoprotein binding and import of lipoprotein derived phospholipids.

The binding of low density lipoprotein (LDL) to the platelet cell membrane could facilitate the transfer of phospholipids from LDL to the platelets. A polyclonal antibody against the platelet glycoproteins IIb/IIIa inhibited the high affinity binding of 125I-LDL by up to 80%. The transfer of pyrene (py)-labeled sphingomyelin (SM), phosphatidylcholine and phosphatidylethanolamine from LDL to the platelets was unaffected by the antibody. The lectin wheat germ agglutinin (WGA) reduced the binding of 125I-LDL to the platelets by approximately 80%. In contrast, the lectin stimulated the transfer of SM from LDL into the platelets by about three-fold. WGA also specifically augmented the transfer of py-SM between lipid vesicles and the platelets, the stimulation being abolished in the presence of N-acetylglucosamine. Dextran sulfate (DS) increased the specific binding of 125I-LDL to the platelets by up to 2.8-fold. On the other hand, the import of LDL-derived py-phospholipids was unaffected by DS. Together, the results indicate that the phospholipid transfer from LDL to the platelets is independent of the high affinity LDL binding to the platelets and is specifically stimulated by WGA. Thus, the interactions of platelets with LDL phospholipids differ markedly from those with the apoprotein components of the lipoproteins.

Acetylglucosamine↗
PubMed1999

Urea induces macrophage proliferation by inhibition of inducible nitric oxide synthesis.

BACKGROUND: Atherosclerosis is a major cause of morbidity and mortality in chronic renal failure and is associated with the proliferation of macrophages within atherosclerotic lesions. METHODS: Because the progression of atherosclerosis as a consequence of decreased nitric oxide synthesis has been described, we investigated the correlation between the inhibition of inducible nitric oxide synthase (iNOS) by urea, macrophage proliferation as assayed by cell counting, tritiated thymidine incorporation and measurement of cell protein, and macrophage apoptosis. RESULTS: Urea induces a dose-dependent inhibition of inducible nitric oxide synthesis in lipopolysaccharide-stimulated mouse macrophages (RAW 264.7) with concomitant macrophage proliferation. Macrophage proliferation, as determined by cell counting, became statistically significant at 60 mM urea, corresponding to a blood urea nitrogen level of 180 mg/100 ml, concentrations seen in uremic patients. iNOS protein expression showed a dose-dependent reduction, as revealed by immunoblotting when cells were incubated with increasing amounts of urea. The decrease of cytosolic DNA fragments in stimulated macrophages incubated with urea shows that the proliferative actions of urea are associated with a decrease of NO-induced apoptosis. CONCLUSIONS: Our data demonstrate that the inhibition of iNOS-dependent NO production caused by urea enhances macrophage proliferation as a consequence of diminished NO-mediated apoptosis.

Animals↗
PubMed1999

Unusual distributions of body fat in AIDS patients: a review of adverse events reported to the Food and Drug Administration.

This report summarizes postmarketing adverse events reported to the Food and Drug Administration (FDA) that describe unusual or abnormal fat distribution in association with anti-retroviral therapies. Reports associated will protease inhibitors were compared to those associated with non-protease inhibitor antiretroviral therapies. The Spontaneous Reporting System (SRS) and Adverse Event Reporting System (AERS) of the FDA MEDWATCH post-marketing surveillance system served as the database. Four protease inhibitors (saquinavir, indinavir, nelfinavir, and ritonavir) and seven nonprotease inhibitors (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, and delavirdine) were searched for reports relating to: weight increase, unusual fat deposition, Cushing's syndrome, or Cushingoid appearance. Each drug was searched for its "life" from time of initial approval through a uniform database cutoff of March 18, 1998. A total of 62 cases of abnormal fat accumulation were reported in association with one or several of the four approved protease inhibitors compared to three cases reported in association with the seven non-protease inhibitor based therapies. Case descriptions varied, and included abdominal fat accumulation, breast enlargement, thick necks, buffalo humps, multiple lipomatous growths, Cushingoid features, centralized fat redistribution, and mesenteric, omental, and retroperitoneal fat accumulation. Some subjects switched or stopped their antiretroviral therapy, others underwent surgery to remove the fat, and many considered their symptoms disabling. The pathophysiologic mechanism for these events remains unclear and a causal link to a specific drug or drug class is uncertain. Patients and clinicians reporting to the MEDWATCH system, however, have clearly associated the development of abnormal body fat with protease inhibitors as opposed to other antiretroviral therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia--a randomized phase-III study.

Because of the recommendation to avoid the concomitant administration of growth factors and chemotherapy, there is only limited information on colony-stimulating factor (CSF) therapy in acute lymphoblastic leukemia (ALL) induction protocols, in which cytotoxic drugs are administered in divided doses over a prolonged period of time, thus requiring a simultaneous administration of growth factors and chemotherapy. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF; filgrastim) as an adjunct to phase I of induction chemotherapy for adult ALL. Patients (n = 53) were randomized to receive no growth factor or G-CSF (5 microg/kg/d subcutaneously) starting on day 2 of chemotherapy consisting of daunorubicin (45 mg/m2) and vincristine (1.5 mg/m2) on days 1, 8, 15, and 22; L-asparaginase (2500 U/m2) on days 1 through 14; and prednisone (60 mg/m2) on days 1 through 28. A total of 25 patients in the G-CSF group and 26 patients in the control arm fulfilled the inclusion criteria of the study. G-CSF markedly ameliorated neutropenia because the median proportion of days with neutropenia less than 1,000/microL was 29% in the G-CSF group as compared with 84% in the control arm (P < .00005). The median time to reach absolute neutrophil counts (ANC) > or = 1,000/microL was 16 days in G-CSF patients and 26 days in controls (P < .001). More importantly, G-CSF significantly reduced the incidence of febrile neutropenia (12% v 42% in controls, P < .05) and documented infections (40% v 77%, P < .05). No significant differences were found with regard to requirements for red blood cell transfusions and platelet concentrates. A total of 24 of 25 (96%) patients in the G-CSF group and 20 of 25 (80%) evaluable control patients had complete remission after phase I of induction therapy. We conclude that G-CSF can be safely administered as an adjunct to induction therapy of ALL and is clinically beneficial by ameliorating neutropenia and reducing infectious complications.

Adolescent↗
PubMed1997

Colocalization of gold-labeled LDL and fibrinogen on platelets: enhanced fibrinogen binding induced by LDL.

Low-density lipoproteins (LDL) specifically bind to the human platelet integrin-alpha IIb and -beta 3 (Koller et al., J. Biol. Chem. 264: 12412-12418, 1989). We show by electron microscopy (EM) that gold (Au)-labeled LDL bind to sites randomly distributed on the surface of platelets in suspension. Within a few minutes, mobile ligand-receptor complexes are translocated from the surface to the open canalicular system (OCS), which finally centralizes as a broad belt. Binding and translocation of Au-LDL are independent of stimulation of platelets by ADP and are completely reversible. Au-fibrinogen shows a strikingly similar, though agonist-dependent, redistribution behavior. Platelets are markedly activated by LDL. This activation is initiated by the binding of LDL to the plasma membrane receptor, and receptor internalization is probably not required for the activation but may instead be one of its consequences. Coincubation with Au-LDL and Au-fibrinogen results in more pronounced activation. The amount of OCS-localized ligands is significantly increased, most likely reflecting enhanced receptor recycling. The two ligands show a tendency to segregate in separate clusters, indicating differences in their postbinding pathways.

Adenosine Diphosphate↗
PubMed1997

Modified LDL decreases the binding of prostaglandin E2, I2, and E1 onto monocytes in patients with peripheral vascular disease.

Recent data suggest that various eicosanoids including prostaglandins play an important regulatory role in the development of atherosclerotic lesions. Peripheral blood monocytes have been implemented in early atherogenesis because they express receptors specific for modified LDL. In this study we investigated the binding of tritium prostaglandins E2 (3H-PGE2), E1 (3H-PGE1) and I2 (3H-PGI2) onto intact peripheral monocytes isolated from 20 patients (32-71 years) with manifested ischemic peripheral vascular disease stage II according to Fontaine and compared the results with those obtained in 16 healthy volunteers (21-68 years). In control subjects, Scatchard analyses of the binding data indicated a single class of high-affinity binding sites for 3H-PGE2 (maximal binding capacity [Bmax] = 11,400 +/- 3200 sites/cell; dissociation constant [Kd] = 1.3 +/- 0.5 nmol/L) and two classes of binding sites for 3H-PGE1 (Bmax1 = 11,200 +/- 4900 sites/cell, Kd1 = 1.5 +/- 0.5 nmol/L; Bmax2 = 47,800 +/- 6100 sites/cell, Kd2 = 12.8 +/- 5.9 nmol/L) as well as for 3H-PGI2 (Bmax1 = 10,100 +/- 3700 sites/cell, Kd1 = 1.7 +/- 0.7 nmol/L; Bmax2 = 81,200 +/- 5200 sites/cell, Kd2 = 14.2 +/- 6.5 nmol/L). In the patients, an absence of the higher-affinity binding class and significantly (P < .01) fewer lower-affinity binding sites were found for each ligand (PGE2: Bmax = 6600 +/- 3600 sites/cell, Kd = 12.1 +/- 3.2 nmol/L; PGI2: Bmax = 6400 +/- 3100 sites/cell, Kd = 22.1 +/- 8.3; PGE1: Bmax = 5300 +/- 1700 sites/ cell, Kd = 20.5 +/- 7.0 nmol/L). After incubation of monocytes with modified LDL (oxidized LDL or acetylated LDL), the binding of prostaglandins was significantly (P < .01 to P < .001) decreased, whereas native VLDL, LDL, and HDL did not interfere with prostaglandin binding. Prostaglandin-induced adenosine 3'-5' cyclic monophosphate (cAMP) formation by monocytes was significantly (P < .01) lower in patients (the concentrations causing 50% elevation of basal cAMP formation [ED50] were 3.8 +/- 2.4 nmol/L for PGE2, 6.3 +/- 3.5 nmol/L for PGE1, and 5.6 +/- 4.1 nmol/L for PGI2) than in the control subjects (ED50 was 1.6 +/- 1.2 nmol/L for PGE2, 4.8 +/- 2.5 nmol/L for PGE1, and 3.1 +/- 1.4 nmol/L for PGI2). After preincubation with modified LDL, the PG-induced cAMP production by monocytes was remarkably decreased in both patients and control subjects (P < .05). Our results suggest a direct effect of modified LDL on PGE2, PGE1, and PGI2 binding onto monocytes by reducing the number of cell surface-expressed receptors available. Modified LDL also reduces the sensitivity of monocytes to prostaglandins, which results in decreased cAMP production. The complex interactions between prostaglandins and lipoproteins may play an important role during atherogenesis.

Adult↗
PubMed1996

Differential targeting of T- and N-cadherin in polarized epithelial cells.

To test whether glycosyl phosphatidylinositol-linked T-cadherin is a component of cell junctions like classical cadherins, we have examined its distribution and targeting in polarized epithelial cells. In vivo, T-cadherin was detected on the apical cell surface of the chick intestinal epithelium. In cultures of transfected Madin-Darby canine kidney cells, T-cadherin was also expressed apically, whereas classical N-cadherin resided basolaterally. Both cadherins were directly targeted to their respective membrane domains. Mutant proteins were expressed in Madin-Darby canine kidney cells to identify the regions responsible for differential cadherin localization. NDeltacyt, an N-cadherin cytoplasmic domain deletion mutant, was stably distributed basolaterally. This mutant was transported to both the apical and basolateral membrane compartments, followed by preferential removal from the apical surface. T-NDeltacyt, a T-cadherin mutant with the N-cadherin cytoplasmic domain deletion, was localized basolaterally, whereas N-TGPI, a GPI-anchored N-cadherin mutant, resided at the apical domain. The T-cadherin carboxyl-terminal 76 amino acids contain the apical targeting signal and include the signal for GPI anchor attachment. Basolateral localization of N-cadherin is achieved through targeting signals in the cytoplasmic domain. Thus, GPI-linked T-cadherin is not a component of cell junctions, consistent with a function as a recognition rather than a cell adhesion molecule.

Animals↗
PubMed1996

All-trans retinoic acid and short-time, high-dose cytarabine in two children with acute promyelocytic leukemia.

We report on two girls, 3 and 13 years old, with acute promyelocytic leukemia (APL) who were successfully treated with all-trans retinoic acid (ATRA) 45 mg/m2/day. "Retinoic acid syndrome" was prevented with short-time treatment of high dose (4 x 1.5 g/m2) cytarabine. This regimen was well tolerated, although both children were critically ill. They achieved a complete remission confirmed by light microscopy, but reverse transcriptase polymerase chain reaction remained positive after ATRA, underlining the need of further chemotherapy.

Adolescent↗
PubMed1995

FMS hemizygosity in myeloid dysplasia and acute myeloid leukemia with chromosomal aberration del(5)(q) demonstrated by polymerase chain reaction.

Interstitial deletions of the long arm of chromosome 5 del(5)(q), are recurring aberrations in the myelodysplastic syndrome and acute myeloid leukemia. Several genes located in region (5)(q23-34) have been implicated as being of pathogenic importance. In this study seven samples of six patients with myelodysplastic syndrome and acute myeloid leukemia who have the del(5)(q) aberration were analyzed by polymerase chain reaction (PCR) and Southern blot technique. FMS hemizygosity was demonstrated in all patients. PCR analysis from peripheral blood samples confirmed the observations of this aberration found by semiquantitative Southern blot. PCR-based analysis can be used for primary diagnosis in addition to cytogenetic evaluation and for follow-up in patients with del(5)(q) aberration.

Acute Disease↗
PubMed1995

Early detection of minimal residual disease by reverse transcriptase polymerase chain reaction predicts relapse in acute promyelocytic leukemia.

The PML/RAR alpha fusion RNA can be detected in acute promyelocytic leukemia (APL), cytogenetically characterized by the translocation t(15;17). Our study included ten newly diagnosed patients with APL who were investigated during the course of their diseases using reverse transcription polymerase chain reaction (RT-PCR). At diagnosis, aberrant fragments with a size heterogeneity due to alternative spliced products were detected in all patients, we observed breakpoints within bcr3 (short type) in two patients and bcr1 and 2 breakpoints (long type) in eight patients. Treatment consisted of all-trans retinoic acid (ATRA) in all patients; six patients received simultaneous cytostatic therapy during remission induction. At the time of complete hematological remission (CR), only two patients showed a negative RT-PCR result; eight of the ten patients were still PCR positive when nested primers were used. Subsequently, eight patients received consolidation chemotherapy and became PCR negative. Seven of eight patients are in continuous complete remission (median remission duration: 21 months, range: 11+ -26+ months). One patient of the chemotherapy group became PCR positive after 4 months in complete remission and relapsed after 6 months. The remaining two patients who were treated only with ATRA relapsed, received induction chemotherapy, and are in second and third complete remission, respectively. In conclusion. PCR negativity can be achieved only by chemotherapeutic consolidation; patients treated with ATRA alone remain PCR positive. Relapse is always preceded by a positive PCR result. Surprisingly, also patients without measurable PML/RAR alpha-mRNA in sequential analyses after cytostatic treatment became PCR positive and experienced relapse.

Adult↗
PubMed1995

Ifosfamide, mitoxantrone and etoposide (VIM) as salvage therapy of low toxicity in non-Hodgkin's lymphoma.

Patients with non-Hodgkin's lymphoma (NHL) who fail to respond to first-line treatment or relapse after having shown complete or partial remission have a poor prognosis, especially in high-grade NHL. Several salvage regimens show considerable toxicity and a poor long-term outcome. In this retrospective study we analyzed data of 55 patients (34 men and 21 women) with a median age of 66 years (range: 18-89). The combination chemotherapy (VIM) consisted of VP-16 (etoposide) 65 mg/m2, ifosfamide 650 mg/m2 and mitoxantrone 3 mg/m2 and was administered on 3 consecutive days along with mesna as uroprotection. Patients were treated for refractory disease or relapse and did not qualify for high-dose chemotherapy and ABMT. Stages according to the An Arbor classification were: stage I/16, II/4, III/8 and IV/37 patients. Thirty-three patients suffered from high-grade and 22 from low-grade NHL. Toxicity (WHO recommendations) was very mild. High-grade NHL showed a better response rate (18/33, 46%) than low-grade NHL (7/22, 36%). Overall response was 41% (12 CR and 11 PR) with a median duration of 36 months (range: 6-57 months). The combination therapy investigated exhibits mild toxicity even in extensively pretreated or elderly patients. The overall response rate of 41% might be improved by increased dosage and growth factor support.

Adolescent↗
PubMed1995

Characterization of LDL and VLDL binding sites on human basophils and mast cells.

Recent data suggest that basophils and mast cells play a potential role in the processing and accumulation of plasma lipoproteins. This study investigated the interactions of 111In-low-density lipoprotein (LDL), 111In-acetyl-LDL, and 111In-very-low-density lipoprotein (VLDL) with purified primary human blood basophils, immortalized human basophils (KU812 cell line), and a human mast cell line, HMC-1. Binding sites for 111In-LDL resolved into curvilinear Scatchard plots indicating two classes of specific binding sites on primary basophils (Bmax1, 7404 sites/cell; Kd1, 1.9 nmol/L; Bmax2, 39,611 sites/cell; Kd2, 29 nmol/L), on KU812 cells (Bmax1, 8290 +/- 2690 sites/cell; Kd1, 2.4 +/- 0.6 nmol/L; Bmax2, 46,470 sites/cell; Kd2, 33.4 +/- 7.8 nmol/L), and on HMC-1 cells (Bmax1, 7840 +/- 360 sites/cell; Kd1, 1.8 +/- 0.8 nmol/L; Bmax2, 61,450 +/- 9900 sites/cell; Kd2, 28.4 +/- 9.4 nmol/L). On KU812 cells, binding of 111In-LDL was displaced by apolipoprotein (apo)-E-rich high-density lipoprotein (HDL) (IC50, 14 +/- 6 nmol/L), LDL (IC50, 29 +/- 11 nmol/L), VLDL (IC50, 55 +/- 21 nmol/L), HDL2 (IC50, 420 +/- 140 nmol/L), and heparin (IC50, 67 +/- 28 nmol/L), whereas no competition was produced by HDL, HDL3, or acetyl-LDL (IC50, > 1 mumol/L). Western blot analysis using the monoclonal antibody C7 confirmed the presence of the LDL receptor on human basophils and HMC-1 cells. 111In-acetyl-LDL binding sites (scavenger receptor) could be detected neither on human basophils nor on HMC-1 cells. 111In-VLDL bound to a single class of high-affinity binding sites on primary basophils (Bmax, 4320 sites/cell; Kd, 10 nmol/L), KU812 cells (Bmax, 4020 +/- 840 sites/cell; Kd, 8 +/- 3 nmol/L), and HMC-1 cells (Bmax, 6143 +/- 1866 sites/cell; Kd, 4 +/- 2 nmol/L). 111In-VLDL binding was displaced by VLDL > LDL > apoE-rich HDL but not by heparin (IC50 > 1 mmol/L). In the presence of prostaglandin E1, the number of 111In-LDL receptors increased by 150% (P < .05) in the high-affinity range and by 170% (P < .01) in the low-affinity range, whereas the number of 111In-VLDL binding sites remained unchanged. VLDL, LDL, HDL, and the subclasses HDL2 and HDL3 inhibited immunological histamine release by primary normal basophils (n = 3) and mast cells (n = 3). Our results provide evidence for the existence of LDL and VLDL binding sites on human basophils and HMC-1 mast cells. The exact biological and pathophysiological roles of these sites remain to be elucidated.

Basophils↗
PubMed1995

Analysis of peripheral blood progenitor cells demonstrates limitations of minimal residual disease diagnosis in a case of acute promyelocytic leukemia.

Detection of minimal residual disease (MRD) by analysis of the PML-RAR alpha fusion transcript using the RT-PCR method is routinely carried out on peripheral blood and bone marrow of patients with APL (AML, FAB:M3). Therapy aims to achieve repeated negative results in these patients thus confirming clinical complete remission. We report a case of APL in second complete remission in which no leukemic cells had been detected in BM and PB for 20 months, and in which PBPC-pheresis was carried out for future transplantation. In two of five pheresis PML-RAR alpha fusion transcripts were detected. This shows that the residual leukemic population may only reach detection level after enrichment by PBPC-pheresis.

Adult↗
PubMed1994

Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are markedly insulin-resistant, but the molecular mechanisms of these changes and their relationship to the hyperandrogenic state remain to be clarified. Mutations have recently been identified in the insulin receptor gene of patients with extreme forms of insulin resistance associated with hyperandrogenism (eg, type A insulin resistance), and these mutations account for the insulin resistance in such patients. We performed this study to determine whether mutations in the coding portion of the insulin receptor gene were responsible for insulin resistance in PCOS. Insulin binding studies using cultured skin fibroblasts of three obese (body mass index > 27 kg/m2) women with PCOS (ie, mild hyperandrogenemia and chronic anovulation of unknown etiology) and documented insulin resistance showed no apparent abnormalities in either the number or affinity of insulin binding sites. Direct sequencing of all 22 exons of the insulin receptor gene from two of the women with PCOS did not reveal any mutations. Furthermore, both alleles of the gene were expressed at equal levels. In a third insulin-resistant PCOS woman, there was no evidence for a mutation in the coding portion of the insulin receptor gene as determined by denaturing gradient gel electrophoresis (DGGE). We conclude that the insulin resistance in these PCOS women was caused by a defect extrinsic to the insulin receptor.

Adult↗