Biomedical subjects

F Katz

Publications and source records attributed to F Katz.

At least 37 records · Page 2Linked to original sources

PubMed1992

Possible evidence for genomic imprinting in childhood acute myeloblastic leukaemia associated with monosomy for chromosome 7.

Monosomy or deletion of chromosome 7 is a frequent finding in both de novo and secondary acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Based on analysis of deletions of chromosome 7 in such patients, it has been suggested that there is a critical region of the chromosome lying within bands q21-q31. We have examined bone marrow and peripheral blood samples from 10 patients with MDS, AML and biphenotypic acute leukaemia who had monosomy for or rearrangement of chromosome 7, seeking evidence of non-random allele loss that might suggest the presence of imprinted genes on the chromosome. Bone marrow cells from one patient with the infant monosomy 7 syndrome had loss of maternal alleles as did two patients with biphenotypic leukaemia. Five out of five patients with MDS and both patients with de novo AML had loss of paternal alleles. One of the latter patients had a del(7) (q31q36) rather than monosomy 7. These findings suggest that imprinting of a gene(s) on chromosome 7, within the bands q31-q36, may be of importance in MDS and AML. Despite the reported increased incidence of AML amongst relatives of patients with cystic fibrosis (CF) the gene for which lies in chromosome region 7q31, none of the patients nor parents studied here appeared to be carriers of the most common gene mutation seen in patients with CF, the delta F508.

Acute Disease↗

PubMed1991

Analysis of ras gene mutations in childhood myeloid leukaemia.

Previous studies have shown that approximately 30% of adult acute myeloid leukaemias and 20% of adult acute lymphoid leukaemias contain point mutated ras oncogenes. In order to assess whether ras oncogenes are also involved in childhood leukaemias, we have used polymerase chain reaction (PCR) amplification and synthetic oligonucleotide probes to study the nature and frequency of ras gene mutations in childhood leukaemias, concentrating largely on the acute myeloid leukaemias (AML). Thirty-four childhood presentation AML DNAs were screened for mutations in and around codons 12, 61 and 117 of N-, K- and H-ras. Eight of these samples (24%) contained ras mutations. As in the adult disease, the gene predominantly involved was N-ras (6/8), with occasional activation of K-ras (2/6). The most common base change was a G----A transition at codon 12 or 13 (4/8). Of the patients with mutant ras, 4/8 were diagnosed as AML FAB subtype M5. Five of the 34 childhood AMLs analysed displayed abnormalities of chromosome 7. However, none of these cases contained a mutant ras gene. One AML patient was studied at relapse, 14 months after initial presentation. The presentation mutation (N61p3) was not detectable, although a new mutation (N13Cys) was readily identified. This observation extends our original finding with presentation and relapse samples of adult AML, in which it was uncommon for the relapse sample to contain the same ras mutation as the presentation DNA. In addition, two out of five patients diagnosed as juvenile CML, were found to harbour mutant ras.

Acute Disease↗

PubMed1991

Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission.

Patients in first remission of acute lymphoblastic leukaemia (ALL) considered to be at high risk of relapse were offered autologous bone marrow transplantation (ABMT) using purged marrow as a therapeutic alternative to cranial irradiation and maintenance chemotherapy. Twenty-seven bone marrows taken in remission, were purged using monoclonal antibodies (anti CD7 for T lineage and anti CD10 and/or anti CD19 for B lineage leukaemias) plus rabbit complement. Retrospective analysis of 19 purged marrows by immunophenotyping or immunoglobulin gene rearrangement studies demonstrated no evidence of disease. Engraftment was seen in 26 of the patients. No correlation was found between the numbers of infused nucleated cells or colony forming units-granulocyte-macrophage (CFU-GM) and subsequent engraftment kinetics. The actuarial disease-free survival (DFS) is 32% at 7 years (median follow-up 3.4 years). There were two transplant related deaths (actuarial risk 8%); the main cause of treatment failure has been disease recurrence with an overall actuarial risk of 67%; 76% for T-ALL (five of nine), 62% for common ALL (five of 10), two of five pre B and none of three patients with B-ALL. In these 27 high risk patients in vitro purging of remission marrow as part of ABMT appears not to improve patient outcome, although confirmation of this would require a randomized trial.

Adolescent↗

PubMed1991

Alpha interferon gene deletions in adults, children and infants with acute lymphoblastic leukemia.

DNA from 76 cases of acute lymphoblastic leukemia (ALL) was tested with a cDNA probe encoding the alpha 2B interferon (IFN) gene transcript. Deletions were found in three of ten pre-B, three of 21 T-cell, four of 22 common and one of 23 null ALL cases. Amongst those with null ALL were 20 infants, most with characteristic translocations, none of whom had deletion of alpha IFN genes. The results confirm that alpha IFN gene deletions may occur without visible abnormalities of chromosome 9p and show that they occur across a wide range of ALL phenotypes. The results suggest that alpha IFN gene deletions may be rare events in null ALL of infants but their incidence and cellular consequences remain unknown.

Adult↗

PubMed1990

Interleukin 7 and interleukin 4 stimulate human thymocyte growth through distinct mechanisms.

One of the major functions of cytokines is their ability to regulate cell growth and differentiation. The complexity of this process has been highlighted by recent studies on murine thymocytes; it has been shown that a number of cytokines interact to regulate thymocyte growth. We have investigated the effects of interleukin 4 (IL-4) and interleukin 7 (IL-7) on human thymocyte proliferation. Although maximal proliferation was dependent upon the presence of the mitogen phytohaemagglutinin (PHA), IL-7 alone stimulated thymocyte growth. In order to determine if this proliferation was due to the induction of IL-2, this pathway was inhibited by the addition of blocking antibody to the IL-2 receptor. Proliferation induced with IL-7 plus PHA, but not that induced by IL-7 alone, could be blocked by this treatment. In contrast, IL-4 stimulated thymocyte proliferation only in the presence of PHA; this proliferation was not inhibited by antibodies to the IL-2 receptor. Our findings show that both IL-7 and IL-4 can act as growth factors for human thymocytes, and that these cytokines stimulate proliferation through distinct mechanisms.

Cell Division↗

PubMed1990

The use of locus-specific minisatellite probes to check engraftment following allogeneic bone marrow transplantation for severe combined immunodeficiency disease.

The graft status of 14 patients, 13 of whom had received an allogeneic bone marrow transplant (BMT) for severe combined immunodeficiency disease (SCID) and one patient with SCID in whom intrauterine maternal engraftment was suspected, was examined using bone marrow or peripheral blood DNA and a combination of locus-specific minisatellite probes for the sex-matched and locus-specific and a Y specific probe for the sex-mismatched patients. The sensitivity of the assay systems was such that less than 0.1% recipient DNA was detectable in a background of donor DNA. Graft status could be satisfactorily documented by 2.5 weeks post-transplant and in one case was of particular value as immunological parameters were misleading. In the six long-term survivors of allogeneic BMT for SCID, the use of the locus-specific probes showed total donor lymphoid and myeloid haemopoietic engraftment in five cases and mixed host/donor populations in one case. The diagnosis in approximately 10% of cases of SCID may prove difficult due to engraftment of the fetus by maternal cells. Diagnosis may be facilitated by the use of the locus specific minisatellite probes and indeed we found specific evidence for such maternal engraftment in one patient at presentation. The combination of these probes together with a Y specific probe thus provides a rapid and accurate method of assessing graft take following allogeneic BMT for SCID. The simple pattern of inheritance obtained and the high level of sensitivity of detection of low numbers of allogeneic cells make the techniques amenable for use in any routine DNA diagnostic laboratory.

Bone Marrow Transplantation↗

PubMed1989

Multiple cAMP-binding proteins in Aplysia tissues.

While it is recognized that cAMP is able to regulate distinct cellular processes differentially, the molecular basis for the diversity of its effects remains unclear. Using photoaffinity labeling with 32P-8 azido-cAMP and two-dimensional gel analysis, we have identified 26 electrophoretic variants of cAMP-binding proteins in the six different tissues of the marine mollusc Aplysia californica sampled. Some of these proteins are found in most tissues, others only in a few; still others appear to be restricted to a single tissue. All of these proteins bind cAMP specifically. The two-dimensional polyacrylamide gel electrophoretic patterns of binding proteins seen in the different tissues fall into three classes. One pattern is shared by the nervous system and embryos. The second is found in muscular tissues (heart, buccal muscle, siphon, and gill). The third pattern is specific to sperm. The presence of distinct subsets of cAMP-binding proteins in different tissues suggests that at least some of the diversity in cAMP's regulatory function may result from diversity in the proteins that bind it.

Animals↗

PubMed1989

The use of DNA probes to monitor minimal residual disease in childhood acute lymphoblastic leukaemia.

DNA probes to both the joining region (JH) of the immunoglobulin heavy chain gene (IgH) and to the beta chain of the T-cell antigen receptor complex (TCR) have been used as tumour-specific markers to monitor the rearrangements of the IgH chain gene and the TCR beta gene in the blast cells of children presenting with acute lymphoblastic leukaemia (ALL) of B or T cell origin. Blast cells from 68 children with early B cell ALL and eight with T-ALL were examined at presentation, at day 28 after commencement of therapy and at varying times thereafter. An additional 43 patients (42 with B cell ALL, one with T-ALL) were studied both at presentation, at completion of their 2-year treatment course and 3 months later. Twelve patients, drawn from both these groups, were studied at relapse as were a further eight patients in whom an extramedullary relapse had occurred. Persistence of clonally-derived cells as a predictor of early relapse was seen in the day 28 bone marrows of 11/76 newly-diagnosed children (nine early B and two T-ALL) followed by rapid, overt relapse in four of the early B ALL cases. No minimal residual disease (MRD) was detected in bone marrows from any of the 43 patients completing their 2-year treatment course, but six of these subsequently relapsed at varying time periods thereafter. Identical patterns of rearrangement at both presentation and relapse were seen in most cases. Oligoclonality, or multiple IgH chain gene rearrangements was seen in the blast cells of 15% of patients with early B cell ALL. No correlation between oligoclonality, high white count, unfavourable phenotype or abnormal karyotype could, however, be ascertained.

Antigens, Neoplasm↗

PubMed1989

Immunoglobulin and T cell receptor gene rearrangement and expression in B cell acute lymphoblastic leukemia.

Immunoglobulin and T cell receptor gene rearrangement and expression were investigated within B cell acute lymphoblastic leukemias (ALLs) that are thought to be representative of the early stages of normal human B cell development. Although the immunoglobulin heavy chain locus is rearranged in leukemic cells from all of these patients, only cells from pre-B ALL patients express mu chain protein. We have shown, however, that immunoglobulin heavy chain transcripts are expressed at levels similar to those found in normal B cells in all of these leukemic cell types and, in addition, some of the leukemias with a more mature phenotype also express immunoglobulin light chain mRNA. In contrast, leukemic cells which had rearranged T cell receptor gamma chain genes were not found to express gamma chain transcripts, indicating that the transcription of immunoglobulin and T cell receptor genes in these cells may be regulated in a lineage-specific manner.

Burkitt Lymphoma↗

PubMed1988

A carbohydrate epitope expressed uniquely on the cell surface of Drosophila neurons is altered in the mutant nac (neurally altered carbohydrate).

Antibodies against horseradish peroxidase (anti-HRP) recognize neural specific cell surface antigens in Drosophila and other insects. The nature of these antigens was investigated in Drosophila and found to include a complex set of developmentally regulated proteins. Their common epitope appears to be a carbohydrate that shares features with the sugar moiety of pineapple stem bromelain, a plant glycoprotein whose carbohydrate structure has been determined. A mutation was identified that eliminates staining by the antibody in imaginal and adult neural tissue. Tissue specific glycoconjugates, although widespread in the animal kingdom, are little understood. This mutation provides a unique opportunity to address the consequences of altering a neural specific carbohydrate moiety in an otherwise intact and behaving animal. The mutation maps to 84F. A second mutation, contained on the third chromosome balancer, TM3, eliminates anti-HRP staining in embryos. These mutations appear to be separate genes.

Animals↗

PubMed1988

Rearrangement of T-cell receptor and immunoglobulin heavy chain genes in childhood acute mixed lineage leukaemia.

Rearrangement of the beta and gamma chain genes of the TCR gene complex and of the Ig heavy chain genes were examined in three cases of childhood acute mixed lineage leukaemia. Blast cells, classified morphologically as acute lymphoblastic leukaemia (ALL) in one child and acute non-lymphocytic leukaemia (ANLL) in the other two, all co-expressed markers associated with both T (CD7, TdT) and myeloid (CD33) cells. Cytogenetic analysis detected abnormalities associated with myeloid leukaemia. Immunoglobulin heavy chain genes were not rearranged in two patients but a novel rearrangement was seen in the third. No rearrangement of the beta or gamma chains of the T-cell receptor complex were seen. Acute mixed lineage leukaemia may thus arise from a pluripotent precursor cell capable of both lymphoid and myeloid differentiation.

Antigens, Differentiation↗

PubMed1988

Cellular and molecular studies on infant null acute lymphoblastic leukemia.

We have studied the cellular and molecular basis of eight cases of infant null acute lymphoblastic leukemia (ALL). All eight patients were under 9 months of age and presented with leukocyte counts in excess of 60 X 10(9)/L, organomegaly, and in two cases CNS infiltration. Although seven cases were morphologically classified as ALL, one patient had both lymphoid and myeloid features. Phenotypic analysis of leukemic blasts from all patients showed a typical null ALL pattern, ie, CD10 (common ALL antigen)-negative, strongly HLA-DR-positive, and CD19 (B4)-positive. The presence of terminal deoxynucleotidyl transferase (TdT) at presentation was positive in six patients' cells and negative in two. Two patients also expressed the myeloid-associated markers CD33 (MY9) and CD15 (TG1), and coexpression of CD19 and CD33 was confirmed in these two by using dual marker flow cytometry (fluorescence-activated cell sorting). Electron microscopic examination of the same two patients' cells showed the presence of monocytoid blasts that labeled with the pan-B cell antibody B4 (CD19). Short-term culture of one of these patients cells in the presence of phorbol ester resulted in the majority of the cells exhibiting myeloid markers, strong nonspecific esterase positivity, and phagocytic properties. Cytogenetic analysis showed the common feature in 7 of 8 cases to be a break in band 11q23. Molecular analysis of DNA from the blast cells of all eight patients showed rearrangement of the immunoglobulin heavy-chain genes in all cases without, however, any evidence of kappa light-chain rearrangement. T cell receptor genes were present in the germline configuration in all cases. Rearrangements of the c-ets 1 oncogene, which maps to band 11q23, were not detected, thus providing no evidence for involvement of this oncogene in the common disease process. Our data indicate that although infant null ALL may present as a heterogeneous disease the similarity of many features between cases suggests a common derivation from a precursor cell sharing phenotypic and genotypic features of both B and myeloid progenitor cells.

Antigens, Neoplasm↗

PubMed1987

Relationship of factor-induced proliferation to respiratory status in marrow progenitor cells.

We have examined the respiratory status of murine and human marrow progenitor cells proliferating in response to growth factors. Proliferation of fresh marrow cells, which are almost entirely entering terminal differentiation, depends on oxidative phosphorylation as determined by oxygen uptake, lactic acid production, and effect of mitochondrial poisons which within minutes completely prevent incorporation of thymidine. However, marrow progenitors responding to growth factors in in vitro assays can proliferate in the presence of high concentrations of mitochondrial poisons, with mixed granulocyte/macrophage colonies being almost refractory to inhibition. We suggest that marrow anaerobiosis may have a physiological significance and may be of relevance to the aberrant respiration of leukemic cells which are considered to be derived from progenitor populations.

Anaerobiosis↗

PubMed1986

Magnetic microspheres and monoclonal antibodies for the depletion of neuroblastoma cells from bone marrow: experiences, improvements and observations.

Improvements to the original procedure of using a panel of monoclonal antibodies and magnetic microspheres for the depletion of tumour cells from bone marrow are described. These include a completely disposable system for the magnetic depletion of tumour cells coated with magnetic microspheres. Properties of a new series of microspheres are compared with the old M330 beads in their ability to deplete neuroblasts from both model systems and 50 bone marrows harvested from Stage IV neuroblastoma patients. Using human neuroblastoma cell lines labelled with the DNA intercalating, Hoechst dye 33342 a 5% tumour contamination can routinely be removed from 5 X 10(6) - 5 X 10(7) nucleated cells. Analysis of the 50 purged marrows revealed that 10 were visibly contaminated with tumour (by conventional cytology and immunological procedures). In all but one case, tumour cells were removed. In this instance the tumour:bead ratio fell to 1:4 indicating the importance of maintaining a sufficient number of beads in the system. Red cell contamination of marrow was also kept extremely low so preventing possible physical blockade of bead:tumour cell interaction. Marrow engraftment was rapid in this group, apart from patients who had been exposed to high doses of alkylating agents prior to autografting.

Antibodies, Monoclonal↗

PubMed1986

Platelet-derived growth factor stimulates growth of highly enriched multipotent haemopoietic progenitors.

Platelet-derived growth factor (PDGF) has been shown to stimulate growth of normal and malignant fibroblasts, glial cells and smooth muscle cells. A growth promoting effect on human haemopoietic precursors has also been described, but the interpretation of this haemopoietic proliferative response to PDGF has been hampered by the lack of purity of the target population. In this study we show that PDGF promotes growth of early bone marrow haemopoietic progenitors depleted of either monocytes or T lymphocytes which are known to influence haemopoiesis. Moreover, the action of PDGF is even increased on a highly enriched BI-3C5 early bone marrow population. BI-3C5 is a novel monoclonal antibody which recognizes an antigen present on all multilineage colony-forming cells (CFU-mix) (Tindle et al. 1985). BI-3C5 positively and negatively sorted fractions were obtained by fluorescence activated cell sorting (FACS) and PDGF was found to stimulate growth of CFU-mix in the BI-3C5-positive fraction (consisting of only 4-6% of the marrow population), the effect being more marked than that on unsorted bone marrow. The results suggest that the product of the cellular proto-oncogene c-sis (the putative structural gene for the beta chain of PDGF) may play a regulatory role in the in vivo proliferation of multipotent haemopoietic progenitors.

Adult↗

PubMed1985

The effect of the leukemic cell line HL60 and acute myeloblastic leukemic cells before and after induction of differentiation on normal pluripotent hematopoietic progenitors (CFU-GEMM).

A leukemic cell line (HL60) and acute myeloblastic leukemia (AML) cells from six patients were co-cultured with normal marrow cells to assess their effects on growth of normal CFU-GEMM. The effects of the following inducers: 12-0-tetradecanoyl-phorbol-13-acetate (TPA), retinoic acid (RA), dimethylsulphoxide (DMSO), 1-25 (OH) D3 (Vitamin D3) and PHA-LCM on both the HL60 and AML cells, were studied. Inhibition of growth of normal CFU-GEMM was observed in the co-cultures in the presence of 1 X 10(4) HL60 or AML leukemic cells/ml. This inhibition was reversed by pretreating the HL60 line with vitamin D3, TPA and RA. No effect on growth of CFU-GEMM was noted when DMSO and PHA-LCM were used. AML cells were morphologically induced to differentiate by TPA or RA in all six cases. In three cases, reversal of inhibition of growth of normal pluripotent hemopoietic progenitors occurred and in three the inhibition of growth persisted. Regulation of inhibition by different inducers did not seem to correlate in all cases with morphological differentiation.

Cell Differentiation↗

PubMed1985

Cardiovascular risk factors and cardiovascular death in haemodialysed diabetic patients.

In a retrospective study, causes of death and the cardiovascular risk conferred by established risk factors were analysed in 200 diabetic and 200 matched non-diabetic uraemic patients admitted for haemodialysis. Total and cardiovascular mortality was considerably higher in diabetics, both type I (4.8-fold) and type II (3.0-fold). Fifty-eight per cent of deaths in diabetics, but only 38 per cent of deaths in non-diabetics were due to cardiovascular causes; myocardial infarction and stroke accounted for less than 15 per cent of deaths, the majority being due to sudden death. Cardiovascular death in diabetes was predicted by both history of hypertension and by cardiomegaly, but to a much lesser extent by clinical evidence of macroangiopathy. The results are compatible with an important role of non-coronary cardiomyopathic mechanisms of cardiovascular death in dialysed diabetics.

Cardiovascular Diseases↗

PubMed1985

Nerve growth cones isolated from fetal rat brain. II. Cyclic adenosine 3':5'-monophosphate (cAMP)-binding proteins and cAMP-dependent protein phosphorylation.

Cyclic adenosine 3':5'-monophosphate (cAMP)-binding proteins and cAMP-dependent protein phosphorylation were examined in growth cone particles (GCPs) prepared from fetal rat brain. Several major proteins which specifically bind a photoactivatable analogue of cAMP are observed in GCPs and correspond to isoelectric variants of the regulatory subunits of the cAMP-dependent protein kinase described in adult brain. We found no evidence for differential compartmentalization of specific cAMP-binding proteins in subcellular fractions of fetal brain or within GCPs. cAMP-stimulated phosphoproteins of GCPs are similar to cAMP-dependent protein kinase substrates characterized in nerve terminals (synaptosomes) of adult brain and include the nerve terminal-specific protein, synapsin I. However, as shown in the companion paper (Katz, F., L. Ellis, and K. H. Pfenninger (1985) J. Neurosci. 5: 1402-1411), this synaptic phosphoprotein is not the major kinase substrate in the GCP fraction. The finding of synapsin I in a subcellular fraction prepared from fetal brain suggests that components of the mature nerve terminal are already present in fetal brain during neuronal sprouting and prior to synaptogenesis.

Animals↗