Biomedical subjects

E L Sievers

Publications and source records attributed to E L Sievers.

27 records · Page 2Linked to original sources

PubMed1997

Expression of sialosyl-T and disialosyl-T antigens in erythroid cells.

Expression of T, sialosyl-T and disialosyl-T antigens on normal blood and bone marrow cells as well as transformed cells was examined using specific monoclonal antibodies and multidimensional flow cytometry. Both anti-sialosyl-T (QSH1) and anti-disialosyl-T (QSH2) monoclonal antibodies aggregated erythrocytes. The anti-disialosyl-T antibody was specific for the erythroid lineage and did not react with neutrophils, monocytes or T-lymphocytes, while the anti-sialosyl-T antibody reacted with erythroid cells and a subset of T-lymphocytes. The developing erythroid cells in bone marrow showed coordinate expression of glycophorin A and the two carbohydrate chains, sialosyl-T and disialosyl-T. Analysis of neoplastic cells showed that the anti-disialosyl-T antibody only reacted with glycophorin A-positive blasts from erythroleukemia (FAB M6) patients (4/4) and one patient with chronic myeloid leukemia in erythroblastic transformation (CMLET). Leukemic blasts from these patients demonstrated coordinate quantitative expression of glycophorin A and disialosyl-T. The anti-sialosyl-T antibody reacted with glycophorin A-positive blasts from FAB M6 patients (4/4) and one CMLET patient; however, the antibody also reacted with glycophorin A-negative blasts from one FAB M6 and the one CMLET patients and transformed cells from other types of leukemia. The anti-T monoclonal antibody (HH8) did not react with any of the other cells tested. These results indicate that glycophorin A and disialosyl-T expression are tightly linked during normal erythroid development and erythroid leukemogenesis.

Antigens, Surface↗

PubMed1996

Patterns of hematopoietic lineage involvement in children with neurofibromatosis type 1 and malignant myeloid disorders.

Children with neurofibromatosis type 1 (NF1) are at increased risk of developing malignant myeloid disorders, particularly juvenile chronic myelogenous leukemia/juvenile myelomonocytic leukemia (JCML/JMML). We investigated bone marrows from 11 such patients (8 boys and 3 girls) and detected allelic losses at the NF1 locus in 4 of them and probable losses in 2 others. To determine which hematopoietic cell lineages were derived from the abnormal clones, Epstein-Barr virus (EBV)-transformed cell lines and CD34+ cells were analyzed from 3 children with JCML with allelic losses in unfractionated marrow. CD34 cells from these 3 patients lacked the normal NF1 allele, whereas EBV cell lines retained it. Erythroblasts plucked from the burst-forming unit-erythroid colonies of one of these children lacked the normal NF1 allele. We also studied a 10-month-old boy with NF1 who developed an unusual myeloproliferative syndrome. His bone marrow and EBV cell line both showed loss of the normal NF1 allele. In our series and in the literature, male sex and maternal transmission of NF1 were associated with the highest risk of myeloid leukemia. These data (1) provide strong genetic evidence that NF1 functions as a tumor-suppressor in early myelopoiesis, (2) confirm the clonal nature of JCML/JMML, (3) suggest that the elevation in fetal hemoglobin seen in JCML/JMML is a result of primary involvement of erythroid progenitors in the malignant clone, (4) show consistent loss of NF1 in the CD34 cells of affected children and show that the malignant clone may also give rise to pre-B cells in some cases, and (5) implicate epigenetic factors in the development of leukemia in children with NF1.

Acute Disease↗

PubMed1996

Prediction of relapse of pediatric acute myeloid leukemia by use of multidimensional flow cytometry.

BACKGROUND: Most patients receiving therapy for acute myeloid leukemia (AML) enter an interval in which leukemic blast cells cannot be detected by light microscopy (i.e., morphologic remission). However, many of these patients experience a subsequent relapse. Multidimensional flow cytometry, which allows the discrimination of antigens expressed on normal and malignant cells, can detect small numbers of cancer cells in bone marrow or peripheral blood specimens. This technique enables the detection of one leukemic blast cell among 10(3) to 10(2) normal regenerating hematopoietic cells. PURPOSE: We determined whether the presence of residual leukemic blast cells, identified in the bone marrow of pediatric patients with AML by use of multidimensional flow cytometry, would be predictive of subsequent leukemic relapse. METHODS: Multidimensional flow cytometry was performed on 205 marrow specimens collected throughout the course of treatment from 39 patients who had achieved morphologic remission. The analyses employed monoclonal antibodies directed against CD45 in combination with mixed pairs of monoclonal antibodies directed against 10 other antigens. A time-varying Cox regression analysis that controlled for sample time intervals, age, sex, morphologic classification of disease, and white blood cell count at diagnosis was used to relate the multidimensional flow cytometric results to the risk of relapse after achieving remission. Reported P values are two-sided. RESULTS: Thirty-five of the 39 patients had bone marrow specimens available from the time that first morphologic remission was achieved. Leukemic blast cells were detected in the specimens from 19 (54%) of these 35 patients. Twenty-five of the 35 patients did not receive an allogeneic (i.e., from a different genetic background) bone marrow transplant during first morphologic remission, and 13 of 14 with residual leukemic cells experienced a relapse at a median time of 153 days after diagnosis (range, 48-863 days). Nine of the 11 patients who did not receive an allogeneic bone marrow transplant and lacked evidence of leukemic blast cells at first morphologic remission relapsed at a median time of 413 days after diagnosis (range, 321-794 days). Among the 10 individuals who received an allogeneic bone marrow transplant during first morphologic remission, five were positive for leukemic blast cells and five were negative; one of these patients (positive for leukemic blast cells) experienced a relapse 265 days after diagnosis, and three others died of transplant-related complications. The estimated risk of relapse during intervals of multidimensional flow cytometric positivity (i.e., intervals of remission for which the immediately preceding cytometry measurement was positive) was 2.8 times greater than that during negative intervals (95% confidence interval = 1.1-7.0; P = .02). CONCLUSIONS AND IMPLICATIONS: Multidimensional flow cytometry identifies residual leukemia in more than half of the patients with AML who are in morphologic remission. The detection of leukemic blast cells in these patients by multidimensional flow cytometry is predictive of a more rapid relapse.

Acute Disease↗

PubMed1996

Long-term survival of a patient with primary sellar choriocarcinoma with pulmonary metastases: a case report.

Extracranial metastasis is an unusual complication of most types of primary intracranial tumor. Approximately one-third of reported cases of primary intracranial choriocarcinoma have been associated with pulmonary tumor metastasis. The prognosis of such patients has been uniformly fatal. This report describes a probable long-term survivor of primary intracranial choriocarcinoma wit pulmonary metastasis. The patient had a complete response to combination chemotherapy with cisplatin, etoposide, and bleomycin and is surviving free of disease >3 years from diagnosis.

Antibiotics, Antineoplastic↗

PubMed1996

Non-malignant neutropenia.

Neutropenia occurs when the production of neutrophils by the bone marrow is outpaced by utilization in the periphery. Abnormalities of hematopoietic stem-cell development and decreased proliferation of neutrophil precursors in the marrow can reduce production of neutrophils. Conversely, decreased neutrophil survival in the peripheral circulation can also give rise to neutropenia. Non-malignant neutropenia of acute onset can be caused by infection, antibody-mediated destruction, or an idiosyncratic reaction to a drug. Severe chronic neutropenia is a global, descriptive term for several disorders of varied etiologies in which neutrophil levels are consistently or recurrently at levels less than 0.5 x 10(9)/L. Despite this heterogeneity of origin, administration of recombinant human granulocyte colony stimulating factor to individuals with severe chronic neutropenia results in an increase in neutrophil counts in most patients associated with a significantly improved quality of life.

Humans↗

PubMed1995

Detection of minimal residual disease in acute myelogenous leukemia.

Techniques to assay minimal residual disease are available for most patients with acute lymphoblastic leukemia, non-Hodgkin's lymphoma, breast cancer, Ewing's sarcoma, and others. Today, a few such tests exist for acute myelogenous leukemia (AML). This review evaluates the tests available for assessing minimal residual disease in AML: morphology, growth in vitro, cytogenetics, magnetic resonance imaging, polymerase chain reaction (PCR)-based assays for translocation products, and multiparameter flow cytometry. Of these, multiparameter flow cytometry appears most promising. Studies using multiparameter flow cytometry to identify leukemic cells by aberrant antigen expression have reported a high positive predictive value with regard to the incidence of relapse. In addition, the test is specific, rapid, inexpensive, and applicable to a sufficiently broad group of patients, allowing its use outside of the research laboratory setting. Judicious use of some of the available assays singly or in combination should identify patients harboring residual leukemic cells.

Flow Cytometry↗

PubMed1995

Cell surface expression of the multidrug resistance P-glycoprotein (P-170) as detected by monoclonal antibody MRK-16 in pediatric acute myeloid leukemia fails to define a poor prognostic group: a report from the Childrens Cancer Group.

Expression of the multidrug resistance (MDR-1) gene product, P-glycoprotein (P-170), and the stem cell antigen, CD34, at diagnosis were determined using monoclonal antibodies (MoAbs) MRK-16 and 12.8 respectively, in 130 pediatric acute myeloid leukemia (AML) patients entered onto Childrens Cancer Group (CCG) study CCG-2891. Fluorescein isothiocyanate (FITC) as a second step reagent was employed for the measurement of P-170 expression since it is commonly used in clinical laboratories. Nine of 30 (30%) infant ( < 1 year of age) de novo specimens expressed P-170 at levels > or = 20% of control cells. In contrast, eight of 100 (8%) AML samples from older children ( > or = 1 year of age) expressed the multidrug resistance surface protein at diagnosis. With the exception of one infant, all de novo samples that expressed P-170 also expressed CD34. Pediatric patients of any age with positive P-170 expression using MoAb MRK-16 with a FITC-conjugated second step reagent fared no worse than remaining patients treated on the same treatment with regard to induction failure, incidence of relapse, event-free survival, or overall survival. Further investigation is necessary to determine whether P-170 assay systems with greater sensitivity will distinguish pediatric AML patients with poor prognosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

GATA-1 is expressed in acute erythroblastic leukaemia.

Previous studies have demonstrated the expression of GATA-1 (a DNA-binding nuclear protein) in erythrocytes, megakaryocytes, eosinophils, basophils, mast cells, early marrow progenitor cells and in mouse and human erythroid leukaemia cell lines. We studied 31 bone marrow specimens from patients with acute myeloid leukaemia (AML) for GATA-1 expression by reverse transcriptase/polymerase chain reaction (RT/PCR) analysis. GATA-1 expression was detected in all of the patients with erythroleukaemia, and in one of nine patients with megakaryoblastic leukaemia, but absent from 17 patients with French-American-British (FAB) M1-5 leukaemia. In AML, GATA-1 expression is indicative of differentiation to the erythroid and possibly megakaryocytic lineages, analogous to its expression in normal haemopoiesis.

Bone Marrow↗

PubMed1985

Sequence requirements for self-splicing of the Tetrahymena thermophila pre-ribosomal RNA.

The sequence requirements for splicing of the Tetrahymena pre-rRNA have been examined by altering the rRNA gene to produce versions that contain insertions and deletions within the intervening sequence (IVS). The altered genes were transcribed and the RNA tested for self-splicing in vitro. A number of insertions (8-54 nucleotides) at three locations had no effect on self-splicing activity. Two of these insertions, located at a site 5 nucleotides preceding the 3'-end of the IVS, did not alter the choice of the 3' splice site. Thus the 3' splice site is not chosen by its distance from a fixed point within the IVS. Analysis of deletions constructed at two sites revealed two structures, a hairpin loop and a stem-loop, that are entirely dispensable for IVS excision in vitro. Three other regions were found to be necessary. The regions that are important for self-splicing are not restricted to the conserved sequence elements that define this class of intervening sequences. The requirement for structures within the IVS for pre-rRNA splicing is in sharp contrast to the very limited role of IVS structure in nuclear pre-mRNA splicing.

Base Sequence↗