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Biomedical subjects

A Jacobs

Publications and source records attributed to A Jacobs.

At least 181 records · Page 10Linked to original sources
PubMed1990

[I-MIBG scintigraphy in the diagnosis of neuroblastoma in children].

Since the early eighties, *I-MIBG (= *I-metaiodobenzylguanidine), which is stored in the neurotransmitter storage granules of chromaffin cells, has been increasingly used for the detection of pheochromocytomas and allied sympathoadrenal pathologies. The aim of this paper is to illustrate, by means of clinical examples, the role of *I-MIBG-scintigraphy in child neuroblastoma and to underline its original place, compared with other imaging techniques, in determining the neuro-ectodermal origin of a tumor as well as in establishing the extension of the lesions at the time of diagnosis and during follow-up.

3-Iodobenzylguanidine↗
PubMed1989

c-myc and c-myb oncoproteins during induced maturation of myeloid and erythroid human leukemic cell lines.

c-myc and c-myb mRNAs have been found to be tightly regulated during hemopoietic differentiation. We have studied nuclear c-myc and c-myb oncoproteins through the cell cycle, during macrophage, granulocyte, erythroid, and megakaryocytic differentiation of KG1, HL60, and HEL cells. p62c-myc and p75c-myb content of propidium iodide-stained nuclei was quantitated by flow cytometry using fluoresceinated antibodies CT14-G4 and MB4.3, respectively. In uninduced cells p62c-myc content is highest in HL60, followed by HEL, then KG1, while p75c-myb is highest in HEL, followed by HL60 and KG1. All lines showed a less than 2-fold increment in both oncoproteins over the cell cycle. Macrophage induction of KG1 and HL60 resulted in early increase in both oncoproteins, followed by a decline to less than starting values by 48 h, concurrent with a reduction of S phase cells and the appearance of adherent alpha-naphthyl acetate esterase-positive cells. p62c-myc changes were more pronounced in HL60 and p75c-myb changes in KG1. Different patterns of oncoprotein expression were found when different inducing agents were used for granulocyte differentiation of HL60. Under all conditions, however, both oncoproteins declined to basal levels before granulocyte maturity. Hemin-induced erythroid differentiation of HEL to hemoglobin-containing cells resulted in biphasic p62c-myc and p75c-myb kinetics. In contrast, dimethyl sulfoxide-induced megakaryocytic differentiation of HEL was accompanied by an early and steady decline in both oncoproteins. Despite considerable reduction in oncoprotein levels, HEL cells were still actively cycling at 120 h. It appears that c-myc and c-myb proteins decline with differentiation, well before proliferation ceases in some lineages. The kinetics of the decline differ between the two oncogenes and vary with the lineage induced and the nature of the inducing agent used. The cell cycle distribution of the oncoproteins does not change during maturation. These data suggest disparate roles for c-myc versus c-myb during hemopoietic differentiation and the existence of multiple signal transduction pathways for down-regulation of these genes.

Antibodies, Monoclonal↗
PubMed1989

Effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on single CD34-positive hemopoietic progenitors from human bone marrow.

To determine the extent accessory cells mediate the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on human hemopoietic progenitors in vitro, we added this hemopoietin to liquid cultures of single CD34-positive marrow cells. These were selected on a fluorescence-activated cell sorter using the HPCA-1 (My10) antibody. Myeloid, erythroid and a few mixed clones developed in 13% of wells in the apparent absence of accessory cells at the beginning of culture. Although accessory cells were generated quickly from the myeloid progenitors and could have mediated the action of rhGM-CSF, this was not the case in the majority of the erythroid clones in which no other cell types were recorded. We conclude that rhGM-CSF can act directly on a subset of erythroid progenitors and probably induces a substantial number of myeloid clones directly.

Bone Marrow↗
PubMed1989

Effect of 5637-conditioned medium on peripheral blood granulocyte-macrophage progenitors in normal subjects and patients with the myelodysplastic syndrome.

There was no overall increase in PB-CFU-GM from normal subjects, or MDS patients, when exogenous CSA (5637-CM) was added to the culture medium. However, there was a sub-group of MDS patients (seven of 35) whose PB-CFU-GM numbers were significantly stimulated by 5637-CM. In addition, there were 11 (out of 48) MDS patients with undetectable PB-CFU-GM in assays without exogenous CSA but only two when 5637-CM was added (p less than 0.01). This sub-group is of particular interest as it is known that those without detectable PB-CFU-GM tend to have significantly shorter survival times than others. The mechanism of the functional abnormality is yet to be determined.

Aged↗
PubMed1989

c-myc protein kinetics during growth and differentiation of CD34 (MY10)-positive blast cells from normal human marrow.

We have used flow cytometry to quantitate nuclear c-myc protein, at each phase of the cell cycle, during in-vitro differentiation of CD34-positive stem cells isolated from normal human bone marrow by the monoclonal antibody, MY10. Mean c-myc protein levels in CD34-positive cells, consisting of greater than 70% blasts, are lower than a marrow fraction containing myeloid cells of intermediate maturation, but have an invariant proportional relationship, with regard to nuclear mass, over the cell cycle. The majority of these primitive cells are non-cycling, as revealed by DNA content. Under our assay conditions, nuclear c-myc protein distribution over the cell cycle did not change as these progenitors entered a proliferative phase in culture. In cultures containing factors supporting myeloid maturation, mean G0/G1 p62c-myc levels initially decline, then rise above starting values as promyelocytes and myelocytes differentiate from CD34-positive cells, and as proliferation begins. With further myeloid maturation, and while cell numbers are increasing, c-myc protein continues to increase. C-myc protein kinetics differ in cultures in which macrophages, rather than myeloid cells, predominate. These data indicate that a complex relationship exists between c-myc gene expression and proliferation, maturation and lineage in haemopoietic cells, and lend support to the notion that early down regulation may be causally associated with the differentiation process.

Antigens, CD34↗
PubMed1989

Oncogenes in the myelodysplastic syndrome.

The conversion of normal haemopoietic stem cells to myelodysplastic and then to leukaemic cells is marked by a number of events leading to progressive genetic changes in the abnormal clonal population. Cytogenetic evidence points to abnormalities at specific chromosomal locations, commonly involving chromosomes 5 and 7, where there are a particular concentration of genes directly involved in the regulation of haemopoietic proliferation and differentiation. These include GM-CSF, IL-3, M-CSF, erythropoietin and others. Other genes that may be involved in the preleukaemic process are so-called 'oncogenes' such as met on chromosome 7q and fms on 5q (which codes for the M-CSF receptor) that may be deleted or translocated. The ras gene family is activated by point mutations in a wide variety of malignant states, including myelodysplasia and acute myeloblastic leukaemia. At the present time we do not know the cause of these genetic lesions, their functional significance or the sequence in which they occur.

Humans↗
PubMed1989

Differences in bone marrow cytogenetic characteristics between treated and untreated myeloma.

Clonal karyotypic abnormalities in myelomatosis at initial diagnosis have been widely studied, but little data are available on the karyotypic status following treatment. We have studied bone marrow (BM) from 17 cases of untreated myelomatosis at initial diagnosis and from a further 29 cases who had received chemotherapy with regimens containing alkylating agents. At the time of study all previously treated cases had been off treatment for at least 152 days, had a paraprotein level in plateau phase, had a BM with less than 4% blasts, and in 28 of these 29 cases had less than 20% BM plasma cells. Two cases had more than 15% BM ringed sideroblasts; one other case was transfusion dependent. Clear differences in cytogenetic characteristics between the two groups were seen. At initial diagnosis clonal karyotypic abnormalities were observed in six of 11 accessible cases. All had hyperdiploid clones (of 49-54 chromosomes) and showed characteristic involvement of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. Additional structural rearrangements were present in only two of these cases. Following treatment, clonal abnormalities were seen in 10 of 25 assessible cases, of which only two showed hyperdiploidy (one with a hyperdiploid line, one with an additional derived chromosome). The remaining eight showed hypodiploid or pseudodiploid lines, and seven of these showed complex karyotypes with multiple rearrangements particularly affecting chromosomes 1, 2, 3, 6 and 7. After a minimum follow-up of 16 months, only four of these 10 cases (40%) remain alive compared with 12 of 15 (80%) with a normal karyotype after treatment (P = 0.03). No correlation was observed between the presence of an abnormal karyotype and the total dose or timing of previous therapy, though cases with an abnormal karyotype tended to have received treatment for longer (790 +/- 166 days) than cases with a normal karyotype (486 +/- 50 days). It is not clear whether the ploidy difference between the two groups represents a change in the disease state due to treatment or a direct effect of treatment itself.

Aged↗
PubMed1989

Circulating erythropoietin in patients with myelodysplastic syndromes.

Serum concentration of erythropoietin (Epo) has been measured by radioimmunoassay in 46 patients with myelodysplastic syndromes. There is an overall inverse relationship between the level of Epo and the degree of anaemia but a wide range of Epo response between patients with similar haemoglobin concentrations. No differences were found between the different FAB groups, but the highest Epo levels were found in those patients with erythroid hypoplasia in the bone marrow. It is suggested that the intensity of erythroid activity in the marrow, as well as the degree of anaemia, may be a factor determining serum Epo concentration.

Adult↗
PubMed1989

The application of X-chromosome gene probes to the diagnosis of myeloproliferative disease.

X-chromosome DNA probes for the phosphoglycerate kinase (PGK) and hypoxanthine phosphoribosyl transferase (HPRT) genes were used to study clonality in haemopoietic cells from 63 women with myeloproliferative disease, idiopathic erythrocytosis, secondary erythrocytosis or normal red cell volumes. A total of 25 women (39%) were heterozygous for one of the polymorphisms associated with these genes. Clonality was demonstrated in five out of six patients with polycythaemia vera (PV) and in three other patients with myeloproliferative disease. In all cases of PV, including the patient in whom clonality was not demonstrated, cultures of peripheral blood showed growth of endogenous erythroid colonies.

Clone Cells↗
PubMed1989

Multidrug resistance in haemopoietic cell lines, myelodysplastic syndromes and acute myeloblastic leukaemia.

Resistance to cytotoxic agents is a common clinical problem encountered in the treatment of human myelodysplastic syndromes (MDS) and acute myeloblastic leukaemia (AML). Cellular acquisition of the multidrug resistance (MDR) phenotype confers loss of sensitivity to a wide range of structurally dissimilar anti-neoplastic agents. This state can arise through increased expression of the mdrl (P-glycoprotein) gene. We have used the mdrl gene probe to investigate adriamycin resistant (HL60/AR) and vinblastine resistant (CEM/VLB100) human leukaemic cell lines. In addition, peripheral blood or bone marrow cells from 66 patients with MDS and AML have been screened for gene amplification and 40 cases for increased mRNA expression. P-glycoprotein gene amplification was observed only in the (CEM/VLB100) and not in the HL60/AR on any other leukaemic cell line. Gene amplification was not found in any patient's cells. Eighteen out of 40 patients showed an increase (2----20) of mdrl mRNA expression. These results are not only of significance in understanding the biology of human drug resistance but have practical importance in the design of anti-leukaemic therapy.

Blotting, Southern↗
PubMed1989

Primary acquired sideroblastic erythropoiesis in non-anaemic and minimally anaemic subjects.

Six patients had primary sideroblastic erythropoiesis together with a haemoglobin concentration of 12.0 g/dl or higher. In four cases this was associated with macrocytosis. Other abnormalities included failure of erythroid progenitor growth from peripheral blood in three cases and occasional dysplastic appearances in neutrophils and megakaryocytes. Sideroblastic erythropoiesis seems to be an early manifestation of the myelodysplastic syndrome and may present clinically at a pre-anaemic stage.

Aged↗
PubMed1989

DNA index and karyotype analysis in myelodysplasia.

DNA index (DI) determined by flow cytometry and karyotype determined by conventional methods were obtained on bone marrow samples from 43 haematologically normal subjects and 54 patients with myelodysplastic syndrome (MDS). Twenty one patients had a clonal karyotype abnormality but an additional five had a DI outside the normal range, showing evidence of aneuploidy that was not available from chromsome preparations. When patients were grouped into those with excess chromosomal material, those with diploid karyotypes, and those with a loss of chromosomal material, there was a significant difference among the mean DIs of each group, normal subjects being different from all patient groups. In these patients DI measurements were of value when carried out together with conventional chromsomal analysis in gaining the maximum amount of genetic information when a satisfactory karyotype might not be available or where failure of an abnormal cell population to proliferate might give an incomplete cytogenetic picture. The contribution of non-clonal chromsome loss to the DI is probably significant but has not been quantitated.

Aneuploidy↗
PubMed1989

In vitro growth of myeloid and erythroid progenitor cells from myelodysplastic patients in response to recombinant human granulocyte-macrophage colony-stimulating factor.

Marrow progenitor cells from 14 myelodysplastic (MDS) patients and 17 normal donors were assayed in semisolid cultures supplemented with increasing doses of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or medium conditioned by 5637 bladder carcinoma cells (5637CM). At doses of supplements shown to be optimal for colony formation in cultures of normal marrow, myeloid (day 14) colony numbers were subnormal in 10 of 14 MDS marrows cultured in 5637CM and in 8 of 14 cultures containing rhGM-CSF (2.5 ng/ml). However, a high dose of rhGM-CSF (20 ng/ml) raised myeloid colony numbers in cultures of many MDS marrows, so that 9 of 14 now yielded colonies within the normal range; increased levels of 5637CM failed to do this. Erythroid colony growth was poor in 13 of 14 MDS marrow cultures supplemented with erythropoietin in addition to 5637CM or rhGM-CSF. High concentrations of rhGM-CSF did not increase erythroid growth. These data suggest that myeloid progenitors from the MDS clone may have a decreased responsiveness to hemopoietins which can be overcome at high concentrations of growth factors.

Adult↗