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Biomedical subjects

K M Wood

Publications and source records attributed to K M Wood.

At least 19 recordsLinked to original sources
PubMed2002

Loss of nuclear expression of the p33(ING1b) inhibitor of growth protein in childhood acute lymphoblastic leukaemia.

BACKGROUND/AIMS: p33(ING1b) is a tumour suppressor protein involved in growth control and apoptosis. Suppression of p33(ING1b) expression is associated with the loss of cellular growth control and immortalisation, whereas its overexpression causes cell cycle arrest. Moreover, normal p33(ING1b) expression is essential for optimal function of p53. Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood, accounting for one third of all childhood malignancies. A variety of cytogenetic abnormalities have been described but there is no single abnormality common to all cases. Deregulation of the TP53 pathway is a common genetic abnormality in human malignancies. However, TP53 mutations are uncommon in ALL. It is possible that alternative mechanisms of regulation of the TP53 apoptosis pathway, such as modulation of p33(ING1b) expression, may be important in ALL. The aim of this study was to assess the expression of p33(ING1b) in childhood ALL. METHODS: One hundred and forty five patients with childhood ALL were investigated in this immunohistochemical study of the expression of p33(ING1b). RESULTS: Loss of nuclear expression of p33(ING1b) was seen in 78% of cases. This was associated with increased cytoplasmic expression of the protein. Kaplan Meier survival analysis demonstrated a trend towards a better prognosis for patients with tumours that had lost nuclear p33(ING1b). CONCLUSION: These results suggest that the loss of nuclear p33(ING1b) expression may be an important molecular event in the pathogenesis of childhood ALL.

Adolescent↗
PubMed2000

Monoclonal antibodies recognizing CD5, CD10 and CD23 in formalin-fixed, paraffin-embedded tissue: production and assessment of their value in the diagnosis of small B-cell lymphoma.

AIMS: Assessment of the expression of antigens CD5, CD10 and CD23 can be of value in the differential diagnosis of small B-cell lymphoma. Correct subclassification is important since optimal treatment regimes differ between the subtypes. The aim of this study was to generate monoclonal antibodies recognizing these antigens in paraffin-embedded tissue and to assess their efficacy using a panel of cases of small B-cell lymphoma of various subtypes. METHODS AND RESULTS: For each antibody synthetic recombinant protein and conventional murine hybridoma technology was employed. Monoclonal antibodies effective in formalin-fixed, paraffin-embedded tissue were successfully generated, designated NCL-CD5-4C7, NCL-CD10-270 and NCL-CD23-1B12, respectively. A series of 58 cases of small B-cell lymphoma including examples of each subtype (lymphocytic, follicle centre cell, mantle cell, marginal zone and lymphoplasmacytoid) was assembled and immunostaining for the respective antigens carried out using the monoclonal antibodies produced. Our results indicate that the antibodies are specific for their respective antigens and give the predicted phenotypic profile in the small B-cell lymphoma subtypes. CONCLUSIONS: These novel monoclonal antibodies may be of value in routine diagnostic practice.

Animals↗
PubMed1998

Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB.

The molecular mechanisms underlying Hodgkin's disease remain obscure, but it has been recognized that the neoplastic cells display high levels of constitutively active nuclear NF-kappaB. Here we demonstrate that although nuclear NF-kappaB is transcriptionally active, the Hodgkin cells fail to activate NF-kappaB dependent transcription in response to CD40 ligand. In three Hodgkin cell lines examined each had abnormalities in expression of IkappaBalpha which could account for the deregulated NF-kappaB. Although all three cell lines had greater than normal levels of IkappaBalpha mRNA no IkappaBalpha protein could be detected in the KM-H2 cells, while the L428 cell line contains a C-terminally truncated IkappaBalpha species that fails to associate with NF-kappaB. The HDLM-2 cell line contains a more slowly migrating form of IkappaBalpha that can associate with NF-kappaB, but increasing the level of this protein within the cell fails to inhibit nuclear NF-kappaB. Addition of recombinant IkappaBalpha to nuclear extracts from all three cell lines resulted in complete inhibition of NF-kappaB DNA binding activity and introduction of a plasmid expressing IkappaBalpha into the cells inhibited the transcriptional activity of an NF-kappaB dependent reporter plasmid. Thus the constitutive expression of NF-kappaB in Hodgkin cells is a direct consequence of the abnormal expression of IkappaBalpha rather than changes in NF-kappaB that render it refractory to inhibition by IkappaB proteins. These changes could, at least in part, account for the characteristic activated phenotype of Hodgkin cells and their pattern of cytokine secretion, which determine the pathological appearance and clinical manifestations of Hodgkin's disease.

CD40 Ligand↗
PubMed1997

Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1.

The t(2;5)(p23;q35) translocation, associated with anaplastic large-cell lymphoma (ALCL), results in the production of the nucleolar protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) protein. This report describes an immunocytochemical study of the distribution of ALK and NPM-ALK proteins using a new monoclonal antibody, ALK1, that recognizes a formalin resistant epitope in both the 80-kD NPM-ALK chimeric and the 200-kD normal human ALK proteins. Cytoplasmic and nuclear labeling was seen in the t(2;5)+ SU-DHL-1 and Karpas 299 cell lines. Normal ALK protein expression was restricted to the central nervous system (in scattered neurons, glial cells, and endothelial cells). Two hundred and thirty-nine cases of lymphoma and 80 nonhematopoietic tumors were immunostained. Antibody ALK1 labeled 53.4% (39 of 73 cases) of CD30+ ALCL. A case of ALCL with a t(1;2) translocation was ALK1+. Three cases of CD30- ALCL with prominent nucleoli showed a unique pattern of coarse granular cytoplasmic labeling. All other tumors, including Hodgkin's disease and lymphomatoid papulosis, were ALK1-. These results indicate that reliable immunostaining of routine biopsy material for NPM-ALK and ALK proteins is feasible. Such analysis is of diagnostic importance, especially because t(2;5)+ ALCL cases have a good prognosis with appropriate treatment.

Adolescent↗
PubMed1997

Overcoming the physician group-hospital cultural gap.

In order for integration between physician practices and hospitals to be successful, each will have to overcome cultural differences that have contributed to a sometimes adversarial relationship. Such differences can be attributed to opposing views related to focus, perspective, working environment, decision making, goals, working style, and management style.

Group Practice↗
PubMed1997

Reviewing practice expenses can improve profitability.

Many physician group practices--particularly practices that have been acquired by hospitals and integrated delivery systems--are experiencing expense increases and productivity decreases. Physician group practices can take steps to reverse these unfavorable trends by carefully reviewing and benchmarking practice costs related to physician compensation plans, support staff salaries and benefits, occupancy costs, clinical supply costs, and malpractice insurance. Group practices also can improve cost management and resource utilization by creating an operating budget based on historical expenditures and anticipated revenues and by comparing it with peer benchmarks.

Budgets↗
PubMed1995

Carboxyl-terminal truncation of leucine76 converts heparin-binding EGF-like growth factor from a heparin-enhancible to a heparin-suppressible growth factor.

Previous studies have indicated that heparin differentially regulates heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR) mitogenic activity. To further explore this phenomenon, these mitogens were compared under identical cell culture conditions in two different assays. The results of our present investigation demonstrated that AR-mediated mitogenic activity in the murine AKR-2B fibroblast-like cell line was inhibited by heparin, while HB-EGF activity was enhanced. However, the absolute effect of heparin appeared to be cell type specific since HB-EGF mitogenic activity was not dramatically affected by coincubation with heparin when tested on human dermal fibroblasts. Several studies have indicated that mutation of a conserved leucine in the carboxyl-terminal region of both EGF and transforming growth factor-alpha results in decreased affinity for EGF receptors. Since this leucine is present in the analogous position of HB-EGF, but absent in AR, we examined the effect of deleting this residue by carboxyl-terminal truncation of HB-EGF. Analysis of recombinant forms of HB-EGF demonstrated that HB-EGF can be converted to a heparin-inhibited growth factor if the putative mature form of the protein is truncated by two residues (leucine76 and proline77) at the carboxyl terminus. Further analysis demonstrated that only leucine76 appears to be required for heparin-dependent enhancement of HB-EGF-mediated mitogenic activity, indicating that this amino acid may play a pivotal role in controlling the response of HB-EGF to heparin or related glycosaminoglycan sulfates. Our results also suggest that expression of different HB-EGF forms in vivo could result in the production of HB-EGFs with divergent responses to sulfated glycosaminoglycans and proteoglycans.

Amino Acid Sequence↗
PubMed1995

Domain organization of I kappa B alpha and sites of interaction with NF-kappa B p65.

The DNA-binding activity and cellular distribution of the transcription factor NF-kappa B are regulated by the inhibitor protein I kappa B alpha. I kappa B alpha belongs to a family of proteins that contain multiple repeats of a 30- to 35-amino-acid sequence that was initially recognized in the erythrocyte protein ankyrin. Partial proteolysis has been used to study the domain structure of I kappa B alpha and to determine the sites at which it interacts with NF-kappa B. The data reveal a tripartite structure for I kappa B alpha in which a central, protease-resistant domain composed of five ankyrin repeats is flanked by an unstructured N-terminal extension and a compact, highly acidic C-terminal domain that is connected to the core of the protein by a flexible linker. Functional analysis of V8 cleavage products indicates that I kappa B alpha molecules lacking the N-terminal region can interact with and inhibit the DNA-binding activity of the p65 subunit of NF-kappa B, whereas I kappa B alpha molecules which lack both the N- and C-terminal regions are incapable of doing so. Protease cleavage of the N terminus of I kappa B alpha was unaffected by the presence of the p65 subunit of NF-kappa B, whereas bound p65 blocked cleavage of the flexible linker connecting the C-terminal domain to the ankyrin repeat-containing core of the protein. This linker region is highly conserved within the human, rat, pig, and chicken homologs of I kappa B alpha, and while it has been suggested that it represents a sixth ankyrin repeat, it is also likely that this is a flexible region of the protein that interacts with NF-kappa B.

Ankyrins↗
PubMed1993

Heterogeneity of CD3 antigen expression in T-cell lymphoma.

CD3 antigen expression was studied in a series of 98 T-cell lymphomas, using polyclonal antibodies which recognize this molecule in routinely processed, paraffin-embedded, tissue. We identified 40 cases in which CD3 was present on only a proportion of the neoplastic cells. This phenomenon of heterogeneous CD3 expression was commonest in pleomorphic T-cell lymphomas (22/42 cases) and in CD30 (Ki-1)-positive lymphomas (5/11 cases), and was less frequently observed in mycosis fungoides (4/18 cases) and not seen in T-cell lymphoblastic lymphoma (0/9 cases). CD3 expression was often related to cell morphology, with CD3 antigen being present on the smaller neoplastic cells but absent from the larger ones. The diagnostic significance of these observations is that, on occasion, it may be possible to diagnose a lymphoma as being of T-cell origin in paraffin sections by demonstrating a minor subpopulation of CD3-positive neoplastic cells.

CD3 Complex↗
PubMed1993

The distribution of adhesion molecules in human atherosclerosis.

Chronic inflammatory cells are a recognized component of atherosclerotic plaques at all stages of development. As adhesion molecules play a fundamental role in inflammatory processes, we have carried out an immunohistochemical investigation of the distribution of endothelial leucocyte adhesion molecule-1 (ELAM-1)*, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human atherosclerotic lesions. Autopsy specimens from abdominal aorta and coronary arteries were obtained from 21 cases within 24 h of death. ELAM-1 and ICAM-1 were consistently expressed by the entire intimal endothelium of normal coronary arteries and also by the intimal endothelium overlying aortic fatty streaks. Both coronary artery and aortic lesions showed strong staining for ICAM-1 on and around macrophages. VCAM-1 was not detected on intimal endothelial cells, but strong staining of adventitial lymphoid aggregates for this molecule was seen. This work suggests a role for ELAM-1 and ICAM-1 in mononuclear cell recruitment during atherogenesis.

Adult↗
PubMed1989

Immediate memory functions in reading disability subtypes.

This study examined immediate memory processes in specific reading disability subtypes. Three subgroups (n = 15 in each subgroup) of reading disabled children were examined: (a) perceptual-motor disorder, (b) verbal disorder-general, and (c) verbal disorder-specific (memory). The three groups were matched for age and full scale IQ. All children received a memory-for-colors task (Color Span Test) designed to evaluate intra- and intermodal serial memory functioning. Comparison of memory profiles for the three reading disability subtypes revealed that patterns varied depending on mode of stimulus presentation or response. Although all three groups performed considerably below normative levels on each of the four subtests of the Color Span Test, all subjects performed significantly better on verbally presented items than on visually presented items. The findings were interpreted to suggest that these reading disabled children may not consistently utilize verbal strategies for coding or retrieval of information when stimuli are visually presented.

Child↗
PubMed1988

Kinetics of the interaction of sertraline with the human platelet plasma membrane 5-hydroxytryptamine carrier.

Sertraline, a new selective 5-HT uptake inhibitor showed a mixed pattern of inhibition of human platelet 5-HT uptake with a Ki value of 2.5 nM and K'i value of 25 nM. Imipramine and alaproclate were found to be fully competitive inhibitors of 5-HT uptake with Ki values of 8 and 130 nM respectively. Sertraline was a fully competitive inhibitor of high-affinity [3H]imipramine binding to platelet membranes with a Ki value of 1.3 nM, as was alaproclate and 5-HT with Ki values of 170 and 800 nM respectively. Both sertraline and imipramine, at a concentration of 10 microM caused a fast monophasic dissociation of [3H]imipramine from platelet membranes in contrast to serotonin which caused a slow monophasic dissociation.

1-Naphthylamine↗
PubMed1984

Treatment of bipolar affective illness with zimeldine, a 5-HT uptake inhibitor.

A small group of patients who had been successfully treated with lithium for a number of years were treated with zimeldine in order to determine whether this antidepressant could be substituted for lithium in patients with a bipolar affective illness. The proposed treatment period of 6 months was not reached by any patient due to depression, hypomania, mania or unusual adverse symptoms. The results of this pilot study suggest that bipolar patients being treated with lithium should not then be treated by antidepressants including those which are potent and selective inhibitors of 5-HT uptake.

Adolescent↗
PubMed1984

Isolation and characterization of lymphosarcoma P1798 variants selected for resistance to the cytolytic effects of glucocorticoids in vivo and in culture.

Clonal subpopulations of lymphosarcoma P1798 have been subjected to glucocorticoid selection in vivo and in culture and the glucocorticoid binding and responsiveness of the resistant variants have been compared with those of the parental lines. Cell populations that are resistant to the cytolytic effects of glucocorticoids in vivo exhibit a slightly reduced level of glucocorticoid binding, although nuclear translocation of the hormone-receptor complex is not reduced. Sensitive and resistant tumors exhibit similar kinetics of hormone uptake and dissociation following a single injection of dexamethasone. Selection for glucocorticoid resistance in vivo does not result in an increase in the modal number of chromosomes. Cells that are resistant to the cytolytic effects of glucocorticoids in vivo are completely sensitive to the antiproliferative effects of glucocorticoids in culture. Moreover, dexamethasone increases the expression of mouse mammary tumor provirus in cytolysis-resistant and sensitive cells both in vivo and in culture. Selection for glucocorticoid resistance in culture yields variants with decreased glucocorticoid binding and/or nuclear translocation of the hormone-receptor complex. These cells appear to express classical receptor-defective phenotypes. Nevertheless, cells that are resistant to glucocorticoids in culture undergo cytolysis when treated with glucocorticoids in vivo. These data indicate that, under certain circumstances, different mechanisms may be involved in loss of glucocorticoid responsiveness in vivo and in culture.

Animals↗
PubMed1984

Binding of [3H]imipramine to human platelet membranes with compensation for saturable binding to filters and its implication for binding studies with brain membranes.

Apparent specific binding of [3H]imipramine to human platelet membranes at high concentrations of imipramine showed deviation from that expected of a single binding site, a result consistent with a low-affinity binding site. The deviation was due to displaceable, saturable binding to the glass fibre filters used in the assays. Imipramine, chloripramine, desipramine, and fluoxetine inhibited binding to filters whereas 5-hydroxytryptamine and ethanol were ineffective. Experimental conditions were developed that eliminated filter binding, allowing assay of high- and low-affinity binding to membranes. Failure to correct for filter binding may lead to overestimation of binding parameters, Bmax and KD for high-affinity binding to membranes, and may also be misinterpreted as indicating a low-affinity binding component in both platelet and brain membranes. Low-affinity binding (KD less than 2 microM) of imipramine to human platelet membranes was demonstrated and its significance discussed.

Binding, Competitive↗