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N Russell

Publications and source records attributed to N Russell.

At least 19 recordsLinked to original sources
PubMed2000

P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway.

P-glycoprotein (pgp), which is the product of the MDR1 (multidrug resistance-1) gene, has an established role as a mediator of cytotoxic drug resistance in acute myeloid leukemia (AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7-AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a significant increase in apoptosis in the presence of the pgp-specific antibody UIC2 (mean increase: 58%; range: 11%-95%; P <. 05). Likewise, apoptosis in growth factor-deprived TF1 cells cultured for 30 hours increased 2.5-fold in the presence of 25 microg/mL UIC2. The pgp reversal agent PSC-833 (1 micromol/L) augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to a comparable degree in 6 pgp-ve samples. To determine whether the sphingomyelin-ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific IC(30) (the concentration of daunorubicin that caused apoptotic cell death in 30% of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was significantly more effective at augmenting apoptosis in pgp-ve patient blasts (median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples (median: 7%; range: 0%-27%; P =.028). Cellular accumulation of exogenous SM was associated with apoptosis and also occurred in nonapoptotic patient cells treated with PSC-833. However, this effect was not seen following treatment with the UIC2 antibody. These results indicate that pgp is able to exert a protective effect on AML cell viability and that this is associated with a reduced effect of exogenous SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp independent mechanism to alter SM distribution and to augment apoptosis induced in AML cells by serum and growth factor withdrawal. (Blood. 2000;95:2897-2904)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin's disease: a report on toxicity and efficacy.

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ïfosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.

Adolescent↗
PubMed1999

Mobilisation of peripheral blood stem cells with IVE and G-CSF improves CD34+ cell yields and engraftment in patients with non-Hodgkin's lymphomas and Hodgkin's disease.

The transplantation of mobilised peripheral blood stem cells is associated with more rapid engraftment than marrow transplantation. We have previously reported that G-IVE (G-CSF, ifosphamide, VP-16, epirubicin) improves the yield of CD34+ cells mobilised in patients with lymphoproliferative disorders compared with cyclophosphamide 3 g/m2 and G-CSF (G/CYCLO). In this study we have extended these observations to a larger series of patients including different lymphoma subtypes. Ninety-seven patients undergoing stem cell mobilisation were studied. Forty-two patients with lymphoproliferative disorders received G-IVE for mobilisation and 55 patients G/CYCLO. The median number of mobilised CD34+cells per leucapheresis was significantly higher for those patients receiving G-IVE: 5.82 x 106/kg (0.19-36) compared with 1.2 x 106/kg (0.04-17), P < 0.001 which resulted in a significantly reduced number of leucapheresis procedures performed in the G-IVE group. When patients were analysed dependent on underlying disease G-IVE mobilised significantly more CD34+cells per leucapheresis for all lymphoma types reaching 8.41 x 10(6)/kg (0.2-32) compared to 1.32 x 10(6)/kg (0. 06-17) for patients with high-grade NHL mobilised with G-IVE and C-GCSF respectively (P = 0.012). For patients with low-grade NHL 3. 12 x 10(6)/kg (0.10-24.39) compared to 1.08 x 10(6)/kg (0.04-9.74) were collected (P = 0.04) and for patients with Hodgkin's disease 3.02 x 10(6)/kg (1.48-36) and 1.04 x 10(6)/kg (0.1-12.3) (P = 0.001). Mobilisation with G-IVE resulted in the achievement of clinically significant CD34+ cell thresholds in a significantly higher proportion of patients compared to cyclophosphamide and G-CSF reaching >2.5 x 10(6)/kg CD34+ cells in 88% vs 62% (P = 0.004), >5 x 10(6)/kg in 67% vs18% (P = 0.001) and >10 x 10(6)/kg in 31% vs 14.5% (P = 0.05). Furthermore, an analysis of engraftment demonstrated that there was a significant reduction in the time to achieve platelet counts of >20 and >50 x 10(9)/l in patients receiving each incremental dose of CD34+ cells. We conclude that G-IVE mobilizes significantly more CD34+cells than G/CYCLO in patients with lymphoproliferative disorders. This effect is consistent in patients with high-grade NHL, low-grade NHL and HD and results in fewer failed stem collections and increased CD34+ cells available for transplantation which results in significantly accelerated platelet engraftment post transplant.

Adult↗
PubMed1999

Generation of anti-idiotype immune responses following vaccination with idiotype-protein pulsed dendritic cells in myeloma.

Myeloma cells produce immunoglobulin which is unique to the malignant clone and presents antigenic determinants, or idiotypes, which may function as a tumour-specific antigen. The availability of significant quantities of idiotype protein in the serum makes immunotherapeutic strategies utilizing this protein to generate an anti-idiotype immune response an attractive prospect. We treated two patients with advanced refractory myeloma with a series of four vaccinations using autologous idiotype-protein pulsed dendritic cells combined with adjuvant GM-CSF. The vaccinations were well tolerated with a mild fever post-vaccination in one patient. An idiotype-specific T-cell proliferative response developed in both patients. This T-cell response was associated with the production of gamma-interferon, indicating a TH-1-like response. Furthermore, one patient developed anti-idiotype IgM antibodies. However, no idiotype-specific cytotoxic T-cell response could be demonstrated. Further investigation is warranted to define the optimal conditions for dendritic cell culture and priming to maximize the anti-tumour immune response.

Antibodies, Anti-Idiotypic↗
PubMed1998

The effect of dietary vitamin D3 on the intracellular calcium gradient in mammalian colonic crypts.

A physiological gradient in intracellular calcium ([Ca2+]i) has been hypothesized to exist along the colonic crypt base-mouth axis, which may be involved in the regulation of colonocyte proliferation, differentiation and apoptosis. In addition [Ca2+]i may be modulated by dietary vitamin D3 which is thought to be protective against colorectal cancer. CF1 mice were maintained for 6 weeks on a defined diet containing either high or low vitamin D3. A colonic crypt base-mouth [Ca2+]i gradient of 201 +/- 79 nM (mean +/- SEM, P < 0.05) was observed in animals maintained on a high vitamin D3 diet and was abolished in mice maintained on a low vitamin D3 diet. The [Ca2+]i gradient was independent of extracellular calcium and elevated levels of [Ca2+]i observed in the basal regions of the crypt in animals maintained on low levels of vitamin D3 were also associated with an increase in intracellular calcium stores. Therefore, a [Ca2+]i gradient exists in colonic crypts and is dependent on dietary vitamin D3.

Animals↗
PubMed1998

Spontaneous cervical epidural hematoma: case report.

Spontaneous spinal epidural hematoma (SSEH) is an uncommon cause of acute nontraumatic myelopathy. We report a 14 year-old boy who had tetraplegia on awakening. Diagnosis of spinal epidural hematoma was made by magnetic resonance imaging. Despite spinal cord decompression within 9 h from onset, he remained tetraplegic. No cause for the bleeding was found. The pathogenic hypotheses of SSEH are discussed and the importance of rapid diagnosis and treatment is emphasized.

Adolescent↗
PubMed1997

The use of an all oral chemotherapy (idarubicin and etoposide) in the treatment of acute myeloid leukaemia in the elderly: a report of toxicity and efficacy.

Acute myeloid leukaemia (AML) is predominantly a disease of the elderly but such patients are not always appropriate candidates for intensive intravenous (i.v.) based treatment regimens. The development of the anthracycline idarubicin which is highly effective in the treatment of AML and is active when given orally has made it possible to design anti-leukaemic regimens which may be given orally and be particularly useful in those elderly patients with AML considered unsuitable for standard intensive aggressive treatments. We have assessed an oral regimen combining idarubicin 30 mg/m2 and etoposide 80 mg/m2 for 3 consecutive days as initial treatment in 28 elderly patients with AML (median age 69 years, range 56-81) who were not considered suitable for more intensive i.v. chemotherapy schedules. Following informed consent, two patients died before treatment began and one patient withdrew prior to treatment. Twenty-five patients underwent one to four courses of treatment. The schedule was well tolerated with minor nonhaematological toxicity. The first course was given in hospital, eight of 21 subsequent courses of treatment were given entirely as an out-patient. Eleven patients responded to treatment with nine (36%) achieving complete remission (CR). The median survival for all patients was 3 months, but for the nine who achieved a CR it is 9 months with six patients still alive, five in first CR and one in second CR. We conclude that a combination of idarubicin and etoposide given orally as first-line treatment in elderly patients with AML is safe and effective. In some patients this means treatment and follow-up can be given entirely on an out-patient basis.

Acute Disease↗
PubMed1996

Non-traumatic cerebral hemorrhage in Saudi Arabs: a hospital-based study of 243 cases.

This is a retrospective study involving 243 Saudi Arabs with non-traumatic cerebral hemorrhages confirmed by CT scan. Intracerebral hemorrhages accounted for about 20% of all strokes in this population. THe male to female ratio was 2.74 which is slightly higher than those reported from elsewhere. Peak frequency was around 60 years. Hypertension was the most common cause accounting for 64% of the cases, hemopathies/coagulopathies for 10% and arteriovenous malformations (AVMs) for 6%. THe cause was undetermined in 21% of patients. Amyloid angiopathy was probably underrepresented due to lack of autopsy correlation. The etiologies were, however, age-related with a clear predominance of AVMs and coagulation disorders before the age of 40 years. Hypertensive hemorrhages were located in the putamen in 46% of cases compared to 20% in non-hypertensive patients while 52% of non-hypertensive hemorrhages were lobar in location compared to 20.5% in hypertensives. Early mortality (19%) in our series was relatively low compared to reports from the industrialized world.

Adolescent↗
PubMed1996

Stem cell mobilization in normal donors for allogeneic transplantation: analysis of safety and factors affecting efficacy.

The use of peripheral blood stem cells instead of bone marrow as the source of haemopoietic cells for allogeneic transplantation is being increasingly explored. We have analysed data from 17 normal donors who underwent stem cell mobilization for allogeneic transplantation with an identical protocol using G-CSF at a dose of 10 micrograms/kg/d, with the first leukapheresis (LP) on the day following the fourth dose of G-CSF. Both G-CSF administration and leukapheresis were well tolerated. Donors under-went a median of two leukaphereses (range one to three) and a median of 6.80 x 10(6) CD34+ cells/kg recipient weight (range 2.4-15.6 x 10(6)) were collected. The median number of CD34+ cells per kg donor weight was 6.05 x 10(6), when corrected for a 12 litre leukapheresis, this gave a median total of 3.89 x 10(6) CD34+ cells/kg donor weight. When analysed with respect to factors which might influence the efficacy of mobilization, male donors were associated with a superior yield. The median number of CD34+ cells/kg/LP harvested was 4.96 x 10(6) in males and 2.79 x 10(6) in females (P < 0.05). The results suggested that, given a recipient of 75 kg, in a male donor a single 12 litre leukapheresis should yield sufficient CD34+ cells (4 x 10(6)/ kg), whereas a female donor would be likely to need two leukaphereses. Age was not found to affect donor yield. In summary, these data confirm that leukapheresis is a safe procedure in normal donors and suggest that males may be more efficient mobilizers of stem cells than females.

Adult↗
PubMed1996

A comparison of computerized tomographic staging systems in chronic sinusitis.

A number of different systems exist for staging computerized tomography (CT) scans in rhinosinusitis. The aim of this study was to determine which of four selected staging systems, currently in common use facilitated the highest level of agreement. The systems studied were those by Jorgensen (1991), May and Levine (1991), Lund and Mackay (1993) and Newman (1994). Ten observers independently assessed 10 representative films. In our assessment, the Lund and Mackay system facilitated the highest level of both inter-observer and intra-observer agreement of the four systems tested. We recommend it be adopted as the standard method of measuring the extent of disease, as depicted by CT scanning for chronic. rhinosinusitis.

Chronic Disease↗
PubMed1995

Stroke and pregnancy.

OBJECTIVE: To study the controversial relationship between pregnancy and stroke. Old studies and those from developing countries suggest that pregnancy considerably increases the risk of stroke. METHODS: The records of 946 consecutive cases of stroke observed in Saudi patients in 10 years were reviewed. Cases which occurred during pregnancy or during the first 15 days postpartum were included in the study. RESULTS: Twelve patients (1.3%) were pregnant or in postpartum at stroke onset. They constituted 27% of women of childbearing age. Cerebral infarction was diagnosed in nine cases and cerebral hemorrhage in three. Four patients died. CONCLUSION: The risk of stroke is only marginally increased (x 1.5) in pregnant compared with non-pregnant Saudi women. Many factors including peripartum cardiomyopathy, patent foramen ovale, changes in clotting factors, peripartum angiopathy and vasoactive steroid hormones, could be responsible for this increased risk.

Adolescent↗
PubMed1994

Decreased retinoblastoma protein expression in acute myeloblastic leukaemia is associated with the autonomous proliferation of clonogenic blasts.

We have previously shown that blasts from some patients with acute myeloblastic leukaemia (AML) grow autonomously in vitro and that this growth pattern is related to the production of autocrine growth factors including granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-1 beta. However, another potential mechanism of autonomous growth involves the deletion of growth inhibitory molecules. One such inhibitory protein is the product of the retinoblastoma (Rb) gene which is expressed in normal haemopoietic cells and functions in cell cycle control and as a transcriptional repressor. Deletion of the Rb gene has been reported in various types of malignancy. We have examined the expression of the Rb gene product in blasts from 39 patients with AML by Western analysis. Using an antibody, Rb (Ab-2) which recognizes the C-terminal region, 11/39 samples (28%) failed to express Rb protein. The results of the Western blot analysis were confirmed by flow cytometry using a second antibody, Rb (Ab-1), against residues 300-380 of the Rb protein. Samples from seven of the 11 Rb-negative cases were studied for the expression of Rb mRNA; Rb mRNA was absent in four and three cases were positive. Analysis of the growth characteristics of these cells showed that blasts from 24/39 cases (62%) had partially or totally autonomous growth in a blast cell colony assay. Of these 24 samples with autonomous growth, 10 (41%) were Rb protein negative; in contrast, of the 15 cases with non-autocrine growth only one was Rb protein negative (7%, P < 0.05). Also, in Rb positive blasts, suppression of Rb protein production using an antisense oligonucleotide significantly increased proliferation of clonogenic AML blasts, confirming that the Rb protein acts as a negative regulator of growth in AML blasts. Our data suggest that deletion of Rb protein expression is frequently found in AML and is associated with the acquisition of autocrine growth characteristics, possibly as the consequence of derepression of genes involved in growth control and cytokine production.

Base Sequence↗
PubMed1994

Absence of retinoblastoma protein expression results in autocrine production of interleukin-6 and promotes the autonomous growth of acute myeloid leukemia blast cells.

Blast cells from up to 70% of patients with acute myeloblastic leukemia (AML) exhibit a variable degree of autonomous growth in vitro which is related to the production of autocrine growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Approximately 40% of AML blasts with autonomous growth have been reported to exhibit abnormalities of retinoblastoma (Rb) protein expression. As the Rb protein is a known transcriptional repressor of the IL-6 promoter, we have investigated the relationship between absence of Rb protein and cytokine gene expression in AML. Blasts from 28 patients were studied, 19 were Rb protein positive by Western blot and by flow cytometry for nuclear Rb protein; blasts from nine patients were Rb-negative. Of the 28 specimens tested by RT-PCR, 24 were positive for GM-CSF mRNA, 21 for IL-1 beta mRNA, and 14 for IL-6 mRNA. Only the expression of IL-6 was found to be significantly associated with loss of Rb protein expression (p < 0.02). The relationship between Rb protein and IL-6 expression was further studied by suppressing Rb protein expression with antisense oligonucleotides. In three out of seven blasts so treated, IL-6 mRNA was induced following antisense treatment whereas control sense oligonucleotides had no effect. Blasts from four patients which secreted high levels of IL-6 exhibited in vitro autonomous growth which could be partially suppressed by anti-IL-6. These results suggest that deletion of Rb protein expression is a mechanism that can dysregulate IL-6 expression in leukemic blasts and thus potentiate the autonomous growth of these cells.

Base Sequence↗
PubMed1994

Regulation of Bcl-2 expression and apoptosis in acute myeloblastic leukaemia cells by granulocyte-macrophage colony-stimulating factor.

Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein which can inhibit the onset of apoptosis induced by withdrawal of trophic factors or by antitumour drugs. In some malignant cells bcl-2 expression has been demonstrated to be regulated by specific trophic factors which act to suppress apoptosis. Here we have investigated the effect of exogenous and autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) on both bcl-2 expression and apoptosis in acute myeloid leukaemia (AML) cells. Blasts from 31 patients with AML were studied, this included 21 patients whose cells exhibited variable degrees of autonomous growth in culture and ten patients with non-autonomous growth. Blasts with autonomous growth expressed significantly higher levels of bcl-2 protein, the intensity of fluorescence expressed as soluble fluorochrome per cell was 40.9 +/- 3.6 x 10(3) (mean +/- SD); this compared with an intensity of bcl-2 expression of 19.3 +/- 2.4 x 10(3) for blasts with non-autocrine growth (p < 0.0001 by Mann-Whitney analysis). Blasts with non-autocrine growth rapidly lost viability following 48 h of culture due to the onset of apoptosis. In these cells apoptosis was suppressed by the addition of GM-CSF and bcl-2 protein expression was found to be significantly upregulated. In contrast blasts from patients with autonomous growth and autocrine GM-CSF production failed to show any features of apoptosis in culture. In these cells bcl-2 expression was significantly downregulated following neutralization of autocrine GM-CSF by antibodies. We conclude that bcl-2 expression in AML cells is regulated by GM-CSF, and suggest that the previously demonstrated negative prognostic effect of autocrine growth as a determinant of treatment outcome in AML is in part due to the effect of autocrine GM-CSF in upregulating bcl-2 expression.

Apoptosis↗
PubMed1993

Autonomous growth of blast cells is associated with reduced survival in acute myeloblastic leukemia.

We have previously classified the in vitro growth characteristics of clonogenic blasts from patients with acute myeloblastic leukemia (AML) according to their capacity to proliferate autonomously in a blast cell colony assay. Here we have analyzed whether the presence of in vitro autonomous growth characteristics has any clinical relevance in AML. We have studied 50 patients (age 2 to 64 years), all of whom were treated with combination chemotherapy, excluding patients with a history of antecedent myelodysplasia. Leukemic cells from 34 of 50 patients (68%) exhibited either partial or totally autonomous growth in a blast cell colony assay. Cells from the remaining patients exhibited nonautonomous growth and were either totally dependent on exogenous growth factor (n = 8) or failed to proliferate at all in the culture system used (n = 8). All 50 patients were treated by intensive chemotherapy and 69% achieved complete remission (CR). Patients whose blasts exhibited autonomous growth in vitro had a significantly lower CR rate (57%) compared with the 16 patients with nonautonomous growth (94%, P = .02). White blood cell count was the only other significant factor (P = .03), but in multivariate analysis growth characteristics remains the most important predictor of CR. Actuarial relapse risk is 80% and 42% at 5 years for autonomous and nonautonomous groups respectively (P = .1). Overall disease-free survival is 21.8% and is higher in the nonautonomous growth group at 54.2% compared with 11.3% at 5 years (P = .0015) in the autonomous growth characteristics was found to be the single most important indicator of CR and disease-free survival. Our data suggests that the suppression of autocrine growth factor production may be of value in the treatment of AML.

Adolescent↗