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Biomedical subjects

M Grundy

Publications and source records attributed to M Grundy.

At least 19 recordsLinked to original sources
PubMed2006

DNA repair contributes to the drug-resistant phenotype of primary acute myeloid leukaemia cells with FLT3 internal tandem duplications and is reversed by the FLT3 inhibitor PKC412.

The presence of internal tandem duplications (ITD) mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor influences the risk of relapse in acute myeloid leukaemia (AML). We have investigated DNA repair in FLT3-ITD and wild-type (WT) cells. Using the comet assay, we have demonstrated that the FLT3 inhibitor PKC412 significantly inhibits repair of DNA damage in the MV4-11-FLT3-ITD cell line and FLT3-ITD patient samples but not in the HL-60-FLT3-WT cell line or FLT3-WT patient samples. Following the discovery that transcript levels of the DNA repair gene RAD51 are significantly correlated with FLT3 transcript levels in FLT3-ITD patients, we further investigated the role of RAD51 in FLT3-ITD-AML. The reduction in DNA repair in PKC412-treated FLT3-ITD cells was shown to be associated with downregulation of RAD51 mRNA and protein expression and correlates with the maintenance of phosphorylated H2AX levels, implying that PKC412 inhibits the homologous recombination double-strand break repair pathway in FLT3-ITD cells. Using FLT3-short interfering RNA (siRNA), we also demonstrated that genetic silencing of FLT3 results in RAD51 downregulation in FLT3-ITD cells but not in FLT3-WT cells. This work suggests that the use of FLT3 inhibitors such as PKC412 may reverse the drug-resistant phenotype of FLT3-ITD-AML cells by inhibiting repair of chemotherapy-induced genotoxic damage and thereby reduce the risk of disease relapse.

DNA Repair↗
PubMed2004

Interleukin-1beta maintains an apoptosis-resistant phenotype in the blast cells of acute myeloid leukaemia via multiple pathways.

Blast cell survival in suspension culture is associated with chemoresistance in acute myeloid leukaemia (AML). Autonomous production of IL-1beta by AML blasts is linked with a proliferative response, although its role in survival and hence apoptosis-resistance has not been examined in this disease. Cells that secreted more than 19.7 pg/ml IL-1beta were significantly more resistant to spontaneous apoptosis in 48-h culture than those that produced less than 19.7 pg/ml IL-1beta (P=0.008). Exogenous rhIL-1beta significantly enhanced 48-h survival in 25/29 blast cell samples (P=0.0001). IL-1 receptor ligation is known to activate at least three survival pathways: those mediated by PI-3 kinase, IL-1 receptor-associated kinase (IRAK) and ceramidase. In apoptosis-sensitive AML blasts with a strong survival response to rhIL-1beta, inhibitors of all three pathways down-modulated an IL-1beta-mediated increase in blast survival, but only the inhibition of all three pathways totally eliminated viable blasts. In apoptosis-resistant and apoptosis-sensitive primary AML samples, the three inhibitors all increased apoptosis in vitro after 48 h. Exogenous rhIL-1beta induced the hyperphosphorylation of Bcl-2. It also increased the activation of NF-kappaB in 5/15 blast samples. IL-1beta-mediated survival pathways may be a factor in apoptosis-resistance in primary AML blasts, and may therefore contribute to chemoresistance.

Amidohydrolases↗
PubMed2001

Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis, wild-type TP53, and vicinal thiol/disulfide status.

Nonresponse to remission-induction chemotherapy, which remains a major problem in acute myeloblastic leukemia (AML), has been linked to cellular resistance to apoptosis. Because the apoptosis induced by chemotherapeutic drugs is mediated by loss of mitochondrial transmembrane potential (MTP), it was postulated that sensitivity to mitochondrial membrane depolarization might be heterogeneous in AML. Using the uncoupling agent carbonyl cyanide m-chlorophenylhydrazone (mClCCP), the mitochondrial membrane sensitivity to depolarization (mClCCP concentrations that inhibit 50% of the transmembrane potential [IC(50)]) in AML blasts was measured and demonstrated marked interclonal heterogeneity, with the existence of comparatively sensitive (median mClCCP IC(50), 4 microM) and resistant (median mClCCP IC(50), 10 microM) clones. Furthermore, the mClCCP IC(50) was inversely associated with spontaneous in vitro apoptosis (P =.001). It was high in cases with mutant TP53 and correlated with the total cellular level of the multidrug resistance-associated protein (P =.019) but not of bcl-2, bax, or bcl-x. It was also found that the dithiol oxidant diamide, in contrast to the monovalent thiol oxidant diethyl maleate, increased the sensitivity of mitochondrial membranes to mClCCP. To confirm that TP53 directly affects MTP in leukemic cells and to establish the role of vicinal thiol oxidation in the TP53-dependent pathway, CEM 4G5 leukemia cells with forced, temperature-dependent expression of TP53 were studied. Monobromobimane, which inhibits mitochondrial membrane depolarization by preventing dithiol cross-linking, inhibited depolarization and apoptosis in 4G5 cells. It was concluded that in leukemia, TP53 and vicinal thiol/disulfide status are determinants of mitochondrial membrane sensitivity to depolarization, which is in turn associated with spontaneous apoptosis.

Apoptosis↗
PubMed1997

From apprenticeship to academia: an adult branch programme.

This paper describes aspects of the introduction an adult branch programme of a Diploma of Higher Education in Nursing course in a Scottish college of nursing and midwifery. It is argued that the Diploma of Higher Education in Nursing course represents a move from a so-called apprenticeship approach, that is the Scottish 1982 Modular Scheme of General Training, to a so-called academic approach under the auspices of the Project 2000 proposals which have been described as the most major development in the preparation of nurses in the UK for many years (UKCC 1986). This paper will discuss the challenges and difficulties encountered when designing the theoretical aspects of the course with respect to the nursing component. The implications of some of the major changes within the scheme of preparation for the clinical areas where the students gain experience will also be discussed. It will be suggested that practice supervision, a development of apprenticeship, is the way ahead.

Adult↗
PubMed1996

The implications of nurse i.v. drug administration.

Consideration needs to be given to the impact of new activities on nursing workload. The preparation and administration of IV drugs requires a significant amount of nursing time. Audits undertaken at different times may highlight changes in nursing workload.

Drug Therapy↗
PubMed1992

Hypophosphatasia: a family study involving a case diagnosed from gingival crevicular fluid.

Hypophosphatasia is an inherited disorder characterized by defective mineralization of the skeletal and dental structures of the body and deficient liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. There has been a tremendous advance in our knowledge of this condition over the last decade due to the advent of highly specific DNA probes and novel microanalytic techniques. The purpose of this paper is threefold: to review the dental aspects of current literature about this rare condition; to present a case (and family study) that was diagnosed in a 5-yr-old boy from 0.14 microliters of gingival crevicular fluid, using a new ultrasensitive chemiluminescent assay for the enzyme alkaline phosphatase; and to provide strong evidence for an autosomal dominant mode of inheritance.

Adamantane↗
PubMed1975

An investigation of the centres of pressure under the foot while walking.

The forces under the foot while walking have been measured using a high sensitivity force-plate of the strip-suspended type combined with simultaneous filming of the sole of the foot. The recording of data and the calculation and plotting of results were much simplified by computer aid. Normal and abnormal feet, both barefoot and shod, were investigated in sixteen subjects. It was found that in normal barefoot walking the forefoot carried a total load of the order of three times that of the heel. When footwear was worn the function of the forefoot was progressively reduced as the rigidity of the sole of the shoe increased. Painful conditions of the forefoot also produced a large reduction in the proportion of the total load transferred.

Analog-Digital Conversion↗