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Biomedical subjects

A J Barrett

Publications and source records attributed to A J Barrett.

At least 163 records · Page 9Linked to original sources
PubMed1992

Inhibition of interleukin 1-stimulated cartilage proteoglycan degradation by a lipophilic inactivator of cysteine endopeptidases.

Inactivators of cysteine endopeptidases were tested as inhibitors of the cytokine-stimulated release of proteoglycan from cartilage. The test system consisted of bovine nasal septum cartilage maintained in organ culture, and the stimulus was provided by recombinant human interleukin 1 alpha. L-3-Carboxy-2,3-trans-epoxypropionyl-leucylamido-(4-guanidin o)butane (E64) and L-3-carboxy-2,3-trans-epoxypropionyl-leucylamido-(3-methyl)b utane (Ep475) showed no inhibition at concentrations up to 100 microM. In contrast, trans-epoxysuccinyl-leucylamido-(3-methyl)butane ethyl ester (Ep453), a 'prodrug' of Ep475, was an effective inhibitor. The LL-, LD- and DL-isomers gave significant inhibition at 10 microM, and the DD-isomer was inhibitory at 100 microM. None of the isomers had any detectable effect on protein synthesis or glycolysis, and their inhibitory effects were reversible. Iodoacetate inhibited proteoglycan release by a general toxic effect. Our results suggest that cysteine endopeptidase(s) play a part in cytokine-stimulated cartilage breakdown, but that effective inhibitors must pass through membranes.

Animals↗
PubMed1992

CA074 methyl ester: a proinhibitor for intracellular cathepsin B.

The specificity of compound CA074 [N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-pro line] for the inactivation of cathepsin B was quantified in in vitro measurements with cysteine endopeptidases from cattle, it being found that the compound is a very rapid inactivator of cathepsin B (rate constant 112,000 M-1.s-1), with barely detectable action on cathepsins H, L, and S or m-calpain. Conversion of the proline carboxyl group of the inhibitor to the methyl ester virtually abolished the effect on cathepsin B, and a possible explanation for the importance of the carboxyl is presented on the basis of the tertiary structure of cathepsin B. It was found that CA074 methyl ester (1 microM, 3 h) caused selective inactivation of the intracellular cathepsin B of human gingival fibroblasts in culture, in contrast to other available agents, and we suggest that CA074 methyl ester will be of value in the elucidation of the biological functions of cathepsin B.

Binding Sites↗
PubMed1992

Graft vs. leukaemia reactions in chronic myeloid leukaemia.

A 39-year-old female relapsed 36 months after allogeneic bone marrow transplantation for chronic myeloid leukaemia. Infusion of peripheral blood leucocytes from her bone marrow donor resulted in complete remission, and she remains leukaemia-free 18 months later. This case provides direct evidence for a 'graft vs. leukaemia' (GVL) effect contributing to the eradication of leukaemia after marrow transplantation. Existing evidence for GVL and its possible mechanisms are reviewed.

Adult↗
PubMed1992

The ENZYMEBA test: detection of intestinal Entamoeba histolytica infection by immuno-enzymatic detection of histolysain.

We describe a new, improved test for the detection of intestinal infection by Entamoeba histolytica. The test depends upon immunoadsorption of the E. histolytica cysteine proteinase, histolysain, from faecal samples, and subsequent visual detection of the enzyme by a colour reaction. With samples from 200 volunteers, results agreed closely with those obtained by the conventional microscopic technique, and there were no false positive reactions with samples containing other parasites. The test is suitable for use either in the laboratory or in the field.

Amebicides↗
PubMed1992

Relapse into blast crisis following bone marrow transplantation for chronic phase chronic myeloid leukaemia: a report of five cases.

A proportion of patients receiving allogeneic bone marrow transplants (BMT) for chronic myeloid leukaemia (CML) in first chronic phase relapse; most of these relapses show features of chronic phase disease. We report here a series of five patients seen at a single institution over a 10 year period who developed blast crisis as the first sign of relapse after BMT for CML in chronic phase. The blast cells were myeloid in three cases and lymphoid in two. In one case the relapse may have occurred in cells of donor origin. The possible explanations for this unusual sequence of events include incipient transformation that was not detected before BMT, undetected relapse into chronic phase proceeding into transformation post-BMT, and transformation occurring de novo post-BMT in small numbers of residual leukaemic stem cells.

Adult↗
PubMed1992

HLA-identical sibling donor bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: influence of GVHD prophylaxis on outcome.

We have analysed the results of treating 140 consecutive patients with chronic myeloid leukaemia (CML) in chronic phase by bone marrow transplantation (BMT) using marrow from HLA-identical siblings performed between February 1981 and July 1991. Three different regimens were used sequentially to prevent graft-versus-host disease (GVHD): cyclosporin A (CsA) alone (n = 39), T-cell depletion of donor marrow (n = 51) and CsA with methotrexate (MTX) (n = 50). Eighty-four patients (61%) survive at a median of 49 months from BMT (range 3-120). The actuarial overall and leukaemia-free survivals at 5 years were 52% and 41% respectively. The actuarial probabilities of leukaemia-free survival and haematological relapse at 2 years for the CsA only group were 65% and 4%, for the T-cell depletion group 40% and 41% and for the CsA/MTX group 68% and 6% respectively. For the T-cell depletion group the probability of leukaemia-free survival was significantly lower (P less than 0.001) and the probability of relapse significantly higher (P less than 0.001) than for other methods of GVHD prophylaxis; differences between the other two groups were not significant. Previous reports that T-cell depletion with Campath-1M results in a high rate of relapse are confirmed. Patients in the CsA/MTX group have been monitored with cytogenetic and polymerase chain reaction studies for residual BCR/ABL transcripts. We conclude that the combination of CsA/MTX is currently the best available approach to prevention of GVHD after BMT for CML and in our hands it is not associated with a major risk of relapse.

Adolescent↗
PubMed1992

Oligopeptidases, and the emergence of the prolyl oligopeptidase family.

Oligopeptidases are endopeptidases that are not proteinases in the strict sense, since they do not hydrolyse peptide bonds in proteins, but act only on smaller polypeptides or oligopeptides. These enzymes apparently perform important, specialized biological functions that include the modification or destruction of peptide messenger molecules. Oligopeptidases have few naturally occurring inhibitors, and their distinctive specificity prevents them from interacting with alpha 2-macroglobulin, unlike the great majority of endopeptidases. The specificity of these specialized endopeptidases doubtless depends upon the three-dimensional structure of the active site, but no crystallographic structure is yet available for an oligopeptidase. Study of the primary structure of prolyl oligopeptidase has recently shown that it is a member of a new family of serine-type peptidases most of which are exopeptidases. The alignment of the sequences leads to the identification of some catalytic triad residues that have not yet been elucidated experimentally.

Amino Acid Sequence↗
PubMed1992

Transplants in ALL.

Explore the source record for details and available documents.

Bone Marrow Transplantation↗
PubMed1992

What determines who develops graft-versus-host disease: the graft or the host (or both)?

Considerable experimental data suggest that most, if not all, recipients of conventional (non-T cell-depleted) HLA-identical sibling transplants are likely to develop graft-versus-host disease (GVHD). This is because all donor-recipient pairs are likely to be disparate for numerous non-HLA antigens and because these grafts contain substantial numbers of donor T cells. However, about one-third to one-half of recipients of this type of transplant have little or no GVHD. Here we review recent data in humans suggesting that others factors, like the ability of the host to modulate GVHD reactivity of immune competent cells in the graft, may explain lack of GVHD in some persons. This concept may have implications for preventing and treating GVHD in humans.

Animals↗
PubMed1992

Progress in allogeneic bone marrow transplantation for acute lymphoblastic leukemia in the 1980's: a report from the IBMTR. The International Bone Marrow Transplant Registry.

Among patients with ALL and irrespective of disease state at transplant, highly significant improvements in treatment-related mortality, relapse and leukemia-free survival were observed during the 1980's. Although these results are encouraging, further reductions in treatment-related toxicity and posttransplant relapse are needed to achieve additional advances in the 1990's.

Bone Marrow Transplantation↗
PubMed1991

Structure/function relationships in the inhibition of thimet oligopeptidase by carboxyphenylpropyl-peptides.

Some novel N-[1(RS)-carboxy-3-phenylpropyl]tripeptide p-aminobenzoates have been synthesised as inhibitors of thimet oligopeptidase (EC 3.4.24.15). These compounds are considered to bind as substrate analogues with the Cpp group in S1 and the peptide portion in the S' sites. The most potent inhibitor is Cpp-Ala-Pro-Phe-pAb, which has a Ki = 7 nM. Substitution of Gly for Ala at P1' leads to weaker binding which can be ascribed to increased rotational freedom. Good substrates often have Pro at P2' and Pro is favoured over Ala at this position in the inhibitors, too. When P2' is Pro, Phe is preferred over Tyr and Trp in P3'. The p-aminobenzoate group makes an important contribution to the binding, probably by forming a salt bridge, and removal of the C-terminal negative charge results in much less potent inhibitors.

Alanine↗
PubMed1991

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVE: To compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission. DESIGN: Retrospective comparison of two cohorts of patients. SETTING: Chemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide. PATIENTS: Patients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987. MAIN RESULTS: Similar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related. CONCLUSIONS: These results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Adolescent↗