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Biomedical subjects

S M Davies

Publications and source records attributed to S M Davies.

At least 19 recordsLinked to original sources
PubMed1998

Modulation of lipid polymorphism by the feline leukemia virus fusion peptide: implications for the fusion mechanism.

The structural effects of the fusion peptide of feline leukemia virus (FeLV) on lipid polymorphism were studied, using differential scanning calorimetry (DSC), 31P nuclear magnetic resonance (NMR), and time-resolved X-ray diffraction. This peptide lowers the bilayer to inverted hexagonal phase transition temperature, TH, of dipalmitoleoylphosphatidylethanolamine (DiPoPE) at peptide mole fractions of up to 1.5 x 10(-3) at pH 5.0 and at pH 7.4. The temperature at which isotropic 31P NMR signals for monomethyldioleoylphosphatidylethanolamine (MeDOPE) first occurred is lowered by the FeLV peptide. The amount of isotropic signal seen at 40 degrees C is directly correlated to the peptide:lipid molar ratio. In the peptide-containing samples, more lipid remains in the isotropic state over the whole recorded temperature range. Isotropic 31P NMR signals were observed for DiPoPE in the presence of the FeLV peptide for the entire recorded temperature range of 35-50 degrees C, while pure DiPoPE showed no significant amount of isotropic signal. X-ray studies of DiPoPE show the formation of a new lipid phase with peptide, which is not seen in the pure lipid samples. Disordering of the Lalpha phase is evidenced by broadening of the diffraction peaks, and the hexagonal cell parameter is decreased with peptide present. Our results suggest that the FeLV peptide is increasing the negative curvature of the lipid system, which is thought to be crucial to the formation of highly bent, high-energy structural fusion intermediates, such as the "stalk" model. Fusion activity for this putative fusogenic peptide was also demonstrated, using a resonance energy transfer (RET) lipid mixing assay. To our knowledge, this work provides the first published experimental evidence of both fusogenic activity and effects on lipid polymorphism for the FeLV fusion peptide.

Amino Acid Sequence↗
PubMed1998

Structural plasticity of the feline leukaemia virus fusion peptide: a circular dichroism study.

The secondary structure of the feline leukaemia virus (FeLV) fusion peptide was investigated using circular dichroism (CD). Our results show that this peptide can readily flip between random, alpha-helical and beta-sheet conformations, depending upon its environment. The CD spectrum changes from one characteristic of random coil to predominantly beta-sheet type, and finally to that showing the characteristics of alpha-helical structure on moving from an aqueous solvent, through several increasingly hydrophobic systems, to a highly hydrophobic solvent. Electron microscopy confirmed the presence of beta structure. We propose that the structural plasticity demonstrated here is crucial to the ability of the fusion peptide to perturb lipid bilayers, and thus promote membrane fusion.

Animals↗
PubMed1998

Interaction of substance P with phospholipid bilayers: A neutron diffraction study.

Neutron diffraction has been used to study the membrane-bound structure of substance P (SP), a member of the tachykinin family of neuropeptides. The depth of penetration of its C-terminus in zwitterionic and anionic phospholipid bilayers was probed by specific deuteration of leucine 10, the penultimate amino acid residue. The results show that the interaction of SP with bilayers, composed of either dioleoylphosphatidylcholine (DOPC), or a 50:50 mixture of DOPC and the anionic phospholipid dioleoylphosphatidylglycerol (DOPG), takes place at two locations. One requires insertion of the peptide into the hydrophobic region of the bilayer, the other is much more peripheral. The penetration of the peptide into the hydrophobic region of the bilayer is reflected in a marked difference in the water distribution profiles. SP is seen to insert into DOPC bilayers, but a larger proportion of the peptide is found at the surface when compared to the anionic bilayers. The positions of the two label populations show only minor differences between the two types of bilayer.

Deuterium Oxide↗
PubMed1998

Engraftment of unrelated donor stem cells in children with familial amegakaryocytic thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia is an extremely rare disorder for which bone marrow transplantation offers the only possibility for cure. The pathophysiology is unclear. Two children with familial amegakaryocytic thrombocytopenia underwent unrelated donor transplantation (bone marrow in one, umbilical cord blood in the second) after a preparative regimen of cyclophosphamide and total body irradiation. Both patients failed initial engraftment, required further donor stem cell infusions and are currently well with sustained engraftment, 16 months and 7 months after transplantation, respectively. The difficulty in achieving engraftment of unrelated donor stem cells in these children suggests that in future cases additional measures to achieve engraftment may be necessary, for example, a more aggressive preparative regimen or an increased stem cell dose.

Child↗
PubMed1998

Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia.

It has been unclear whether a graft-versus-leukemia (GVL) effect assists in the control of juvenile myelomonocytic leukemia (JMML) following allogeneic bone marrow transplant. We describe a patient with JMML who relapsed early after an unrelated donor transplant, and following withdrawal of immunosuppression developed graft-versus-host disease (GVHD). Associated with GVHD the proportion of donor cells measured by variable nucleotide tandem repeat (VNTR) analysis increased, and peripheral blasts and cutaneous disease were eliminated. These findings strongly suggest that GVL has a role in the control of JMML.

Bone Marrow Transplantation↗
PubMed1997

Unrelated donor bone marrow transplantation for children and adolescents with aplastic anaemia or myelodysplasia.

Allogeneic transplantation from an HLA-matched family member has been shown to be effective in reconstituting normal haemopoiesis in young people with severe cytopenias, classified as myelodysplastic syndrome (MDS) or severe aplastic anaemia (SAA). Unrelated donor transplant is a therapeutic choice for patients without a suitable family member donor. We report the outcome of seven patients < 20 years old with SAA and 10 with MDS treated with BMT from an HLA A,B DRB1 matched (n = 8) or A or B locus mismatched (n = 9) unrelated donor at the University of Minnesota between March 1988 and August 1995. Primary graft failure occurred in two patients and secondary graft failure in one, who was subsequently successfully engrafted with a second donor marrow infusion. Grades II-IV GVHD occurred in 10/16 (63%), and grades III-IV in 6/16 (37%) evaluable patients. Nine of the 17 patients (six with MDS and three with SAA) survive with full donor chimaerism, a median of 1.2 years post-BMT (range 3 months to 7 years). We recommend early referral for consideration of unrelated donor BMT for young patients with MDS, and patients with SAA without response to immunosuppression.

Adolescent↗
PubMed1997

Unrelated donor bone marrow transplantation for children with acute leukemia.

PURPOSE: To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS: Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS: The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION: URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.

Adolescent↗
PubMed1997

Granulocyte-macrophage colony-stimulating factor receptor-targeted therapy of chemotherapy- and radiation-resistant human myeloid leukemias.

Contemporary therapies for acute myeloid leukemia (AML) commonly fail to cure patients because of the emergence of drug resistance. Drug resistance in AML is multifactorial but can be associated with the overexpression of transmembrane transporter molecules, including P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP), or associated with inactivation of the p53 tumor suppressor gene, as well as overexpression of the anti-apoptotic protein bcl-2. We are investigating if novel recombinant biotherapeutics can circumvent these resistance mechanisms to effectively treat refractory AML. To target the lethal action of diphtheria toxin (DT) to high affinity granulocyte-macrophage colony-stimulating factor (GMCSF) receptors on AML blasts, we have produced a recombinant chimeric fusion toxin, DTctGMCSF. Since DTctGMCSF enters and kills its target cells by unique mechanisms (GMCSF-receptor binding and protein synthesis inhibition) and is not similar in structure to Pgp or MRP substrates, we postulated that it would be an active agent against therapy-resistant AML. DTctGMCSF was selectively cytotoxic (IC50 1-10ng/ml) to GMCSF-receptor positive AML cells expressing the Pgp- or MRP-associated multi-drug resistant phenotypes, despite high level resistance to conventional chemotherapeutic agents. DTctGMCSF also efficiently killed AML cells deficient in p53 expression, as well as radiation-resistant AML cells and mixed lineage leukemia cells expressing high levels of bcl-2. In addition, DTctGMCSF killed > 99% of primary leukemic progenitor cells from therapy-refractory AML patients under conditions that we have previously found to not adversely affect the proliferative capacity or differentiation of pluripotent normal hematopoietic progenitor cells. DTctGMCSF may prove useful in treating myeloid leukemias that are otherwise resistant to a wide range of conventional therapies.

Antineoplastic Agents↗
PubMed1997

A recombinant fusion toxin targeted to the granulocyte-macrophage colony-stimulating factor receptor.

Human granulocyte-macrophage colony stimulating factor (GMCSF) and its high affinity receptor function to regulate the proliferation and differentiation of myeloid lineage hematopoietic cells, and may participate in the pathogenesis of many malignant myeloid diseases. We have used genetic engineering based on the elucidated molecular structures of human granulocyte-macrophage colony-stimulating factor and diphtheria toxin (DT) to produce a recombinant fusion toxin, DTctGMCSF, that targets diphtheria toxin to high affinity GMCSF receptors expressed on the surface of blast cells from a large fraction of patients with acute myeloid leukemia (AML). DTctGMCSF was specifically immunoreactive with antidiphtheria toxin and anti-GMCSF antiseras, and exhibited the characteristic catalytic activity of diphtheria toxin, catalyzing the in vitro ADP-ribosylation of purified elongation factor 2. The cytotoxic effects of DTctGMCSF were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-tetrazolium (MTT) bromide assay of cell viability and in vivo assays of protein synthesis inhibition. DTctGMCSF were specifically cytotoxic to human leukemia cell lines bearing high affinity receptors for human GMCSF with IC50 of 10(-9) to 10(-11) M. It was not toxic to mammalian hematopoietic cell lines lacking human GMCSF (hGMCSF) receptors. In receptor positive cells, cytotoxicity can be specifically blocked by a large excess of hGMCSF, confirming that its cytotoxicity is mediated through the hGMCSF receptor. THough DTctGMCSF inhibited granulocyte-macrophage colony formation by committed myeloid progenitor cells (CFU-GM), it did not significantly affect erythroid burst formation by committed erythroid progenitor cells (BFU-E), or mixed granulocyte-erythroid-macrophage-megakaryocyte colony formation by pluripotent multilineage progenitor cells (CFU-GEMM). DTctGMCSF holds promise for the treatment of myeloid lineage malignancies, and is a useful reagent to study hematopoiesis.

Animals↗
PubMed1997

Polyclonal engraftment after unrelated donor bone marrow and cord blood transplantation.

Data on a small number of allogeneic sibling donor marrow transplants have indicated that reconstituted hematopoiesis can be oligoclonal or even monoclonal, suggesting that hematopoiesis can be reconstituted from a very small number of stem cells. However, other studies have failed to confirm this observation. Animal data indicate that hematopoiesis is likely to be oligoclonal after transplantation using limiting numbers of hematopoietic stem cells, or in cases of poor engraftment. In this study we investigated clonality of engraftment after unrelated donor (URD) bone marrow (BM) and cord blood transplantation, clinical settings in which human leukocyte antigen (HLA) disparities have been known to impair engraftment and in which stem cell numbers have been limiting. Twenty-four URD transplant recipients (20, BM; 4, cord blood) together with 8 sibling donor marrow, 2 sibling donor peripheral blood stem cells (PBSC), and 1 sibling donor cord blood recipients were studied at 28 days, 100 days, 6 months, and 1 year post-bone marrow transplantation (BMT) using the polymerase chain reaction (PCR)-based human androgen receptor assay (HUMARA) as a marker of clonality. URD marrow and cord blood recipients show polyclonal reconstitution in all cases, and results are similar at early and late time points after BMT. Similar results were seen in sibling donor marrow and cord blood recipients. These data indicate that oligoclonal hematopoiesis is not a frequent event after URD stem cell transplantation, even for cases in which limited numbers of stem cells are infused.

Adolescent↗
PubMed1996

Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease.

To reduce the morbidity and mortality associated with unrelated donor bone marrow (BM) transplantation and potentially extend the pool of suitable donors, cryopreserved unrelated donor umbilical cord blood was considered as an alternate source of hematopoietic stem cells for transplantation. Patients with leukemia, BM failure syndrome, or inborn error of metabolism were eligible for a phase I clinical trial designed to estimate the risk of graft failure and severe acute graft-versus-host disease after transplantation of umbilical cord blood from unrelated donors. As of December 21, 1995, unrelated donor umbilical cord blood was used to reconstitute hematopoiesis in eighteen patients aged 0.1 to 21.3 years weighing 3.3 to 78.8 kg with acquired or congenital lympho-hematopoietic disorders or metabolic disease. Patients received either HLA-matched (n = 7) or HLA-1 to 3 antigen disparate (n = 11) grafts collected and evaluated by the New York Blood Center (New York, NY). The probability of engraftment after unrelated donor umbilical cord blood transplantation was 100% with no patient having late graft failure to date. The probability of grade III-IV acute graft-versus-host disease at 100 days was 11%. With a median follow-up of 6 months (range, 1.6 to 17 months); the probability of survival at 6 months is 65% in this high risk patient population. We conclude that cryopreserved umbilical cord blood from HLA-matched and mismatched unrelated donors is a sufficient source of transplantable hematopoietic stem cells with high probability of donor derived engraftment and low risk of refractory severe acute graft-versus-host disease. Limitations with regard to recipient size and degree of donor HLA disparity remain to be determined.

Actuarial Analysis↗
PubMed1996

Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective.

We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related-donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated-donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated-donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft-versus-leukemia effect.

Adolescent↗
PubMed1996

Big babies and infant leukemia: a role for insulin-like growth factor-1?

Several epidemiologic studies have demonstrated that high birthweight is associated with an increased risk of infant leukemia; however, the reason for this relationship is unclear. Biologic data demonstrate that birth weight is correlated positively with circulating levels of insulin-like growth factor-1 (IGF-1). IGF-1 is important in blood formation and regulation and has been shown to stimulate the growth of both myeloid and lymphoid cells in culture. Since infants who develop leukemia are likely to have had at least one transforming event occur in utero, we hypothesize that high levels of IGF-1 may both produce a larger baby and contribute to leukemogenesis.

Birth Weight↗
PubMed1996

Unrelated donor bone marrow transplantation for hematological malignancies-current status.

We have explored the efficacy and toxicity of hematopoietic stem cell transplantation from unrelated donors for hematologic malignancies and other disorders. While most marrow donors have been identified through the National Marrow Donor Program in cooperation with many international registries, the recent development of unrelated donor umbilical cord blood (UCB) banks has allowed us to also evaluate this stem cell source. Analysis of the first 211 URD BMT performed at the University of Minnesota shows an overall survival of 33%, with older recipient age and transplant from a donor with a major HLA-A or B mismatch independently associated with poorer survival. Analysis of engraftment of URD marrow shows increasing risk of delayed or incomplete engraftment with increasing HLA disparity between URD and recipient. GVHD is increased in recipients of URD marrow compared with recipients of related donor marrow. Malignant relapse, however, is less frequent in URD marrow recipients, perhaps due to an increased graft-versus-leukemia effect. Formal assessment shows quality of life in long term URD BMT survivors (beyond 2 years) is excellent, and not different from that seen in sibling marrow recipients. Data from patients receiving unrelated donor UCB transplantation at the University of Minnesota indicate that UCB is an acceptable alternate source of stem cells, at least for young recipients, and may be associated with a reduced incidence of GVHD. Ongoing studies at the University of Minnesota include examination of the applicability of unrelated UCB transplantation to adult recipients, and of the degree of HLA-incompatibility which can be tolerated in UCB transplantation. Studies to identify the optimal GVHD prophylaxis for URD BMT, and to examine the role of class II matching in transplant outcome are in progress.

Bone Marrow Transplantation↗
PubMed1996

Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse.

Twenty-three second bone marrow transplants (BMT) were performed between October 1987 and January 1994 for patients with malignant relapse following initial BMT. For first BMT, twenty-one of 23 (91%) were conditioned with cyclophosphamide plus total body irradiation. For second BMT, a uniform conditioning regimen consisting of busulfan and cyclophosphamide was used. Eleven patients had chronic myelogenous leukemia, seven acute leukemia, four lymphoma, and one myelodysplastic syndrome. Median patient age at second BMT was 32 years, the median time between first BMT and relapse was 22 months, and the median time to second BMT after relapse was 5 months. The second BMT marrow source included: autologous marrow (1), unrelated donors (4), new matched sibling donors (5) and same matched sibling donors as the first BMT (13). The Kaplan-Meier disease-free survival and survival rates at 3 years were 38 and 43%, respectively (median follow-up of survivors was 45 and 48 months, respectively), and five patients survive disease-free at 4-6 years. Nine of the 13 deaths occurred within 100 days after second BMT; eight had relapsed within 1 year of the first BMT. We conclude that: (1) second BMT can offer durable long-term survival in certain patients, especially those who relapse late after first transplant; (2) busulfan and cyclophosphamide is a suitable conditioning regimen for second BMT.

Adolescent↗
PubMed1996

Unrelated donor bone marrow transplantation for Fanconi anemia.

Patients with Fanconi anemia (FA) commonly develop bone marrow failure, which may evolve to myelodysplasia or acute myeloid leukemia (AML). Treatment of these patients is complicated by their marked hypersensitivity to DNA cross-linking agents. In this report we describe the results of allogeneic unrelated donor bone marrow transplantation in seven FA patients, using a low-dose cyclophosphamide (40 mg/kg) and TBI (400-450 cGy) conditioning regimen. Two patients had bone marrow failure with normal chromosomes and no dysplasia prior to transplant. The remaining five had clonal chromosomal abnormalities. One patient had refractory anemia with excess blasts in transformation and two had early AML with 20 and 25% blasts, respectively. Two patients died early (before day 28) without hematological evidence of engraftment, one of veno-occlusive disease and one of infection (fungal). Four of the remaining five patients achieved sustained engraftment after the first marrow infusion; one patient had secondary graft failure requiring repeat marrow infusion but subsequently achieved engraftment. Of five evaluable patients, three had mild (grades I-II) acute GVHD and two had grade IV GVHD, which was fatal in both cases. Two of three evaluable surviving patients have chronic GVHD controlled with immunosuppression. Three patients survive 9 months to 3 years post-unrelated donor BMT: two who had early leukemia and one with severe aplasia at the time of transplant. These data indicate that unrelated donor BMT can be performed successfully in FA patients using cyclophosphamide 40 mg/kg and TBI 400 to 450 cGy, even after evolution to early leukemia. However, significant problems with both GVHD and engraftment remain. Future studies will evaluate the role of T cell depletion in improving the results of unrelated donor marrow transplantation in FA patients.

Adolescent↗