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Biomedical subjects

R Ash

Publications and source records attributed to R Ash.

At least 19 recordsLinked to original sources
PubMed1995

Picrotoxin is a CYP1A1 inducer in rainbow trout hepatocytes.

Picrotoxin is a CYP2B inducer in mammals (1). However, in primary cultures of rainbow trout hepatocytes we showed CYP1A1 gene expression to be strongly induced as characterized by 7-ethoxyresorufin-O-deethylase activity, immunoblots of CYP1A1 protein, and Northern blots of CYP1A1 mRNA. Induction of CYP1A1 in these cells appeared to be via the aromatic hydrocarbon (Ah) receptor as indicated by increased levels of Ah receptor in the nuclear extracts of picrotoxin-treated cells. Picrotoxin induction of CYP1A1 was blocked by actinomycin D. Superinduction of CYP1A1 mRNA occurred in cells treated with cycloheximide. Co-incubation of hepatocytes with picrotoxin and a saturating concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in synergistic increases in CYP1A1 gene expression. These results suggest that picrotoxin induction of CYP1A1 is regulated at the level of transcription and may involve an alternative mechanism(s) to that of TCDD.

Animals↗
PubMed1995

Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation.

Preliminary studies in allogeneic BMT suggest that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is well tolerated. This is a prospective, multicenter, randomized, double-blind, placebo-controlled trial. Yeast-derived rhGM-CSF 250 micrograms/m2/day or placebo was administered by 4-hour i.v. infusion starting on the day of marrow infusion (day 0) to day 20. All patients received HLA-identical sibling marrow and cyclosporine and prednisone for GVHD prophylaxis. Fifty three patients received rhGM-CSF and 56 received placebo. Comparison of demographics revealed no differences. The time to achieve an absolute neutrophil count of > 0.5 x 10(9) cells/l was shortened in rhGM-CSF treated patients (day 13 vs. 17, P = 0.0001). The incidences of grade III-IV mucositis and infection were significantly reduced (P = 0.005, P = 0.001, respectively) and duration of hospitalization was modestly shortened by 1 day (P = 0.02) in rhGM-CSF treated patients. No differences in platelet recovery, erythrocyte recovery, incidence of veno-occlusive disease, GVHD severity, relapse or survival were observed. In conclusion, rhGM-CSF is well tolerated and reduces post-transplant morbidity in patients undergoing HLA-identical allogeneic BMT.

Adult↗
PubMed1995

Selective T cell depletion with CD8-conjugated magnetic beads in the prevention of graft-versus-host disease after allogeneic bone marrow transplantation.

The effects of a new immunomagnetic method of selectively depleting CD8+ lymphocytes from donor bone marrow were studied in 29 patients undergoing transplantation from HLA-identical sibling (n = 20) or alternative (n = 9) donors. The direct immunomagnetic depletion method consistently removed > 95% of CD8+ cells and the non-specific loss of other cell subsets was only about 15%. Recovery of CFU-GM and BFU-e was on average > 100%. The final graft contained 0.9 +/- 0.6 x 10(8)/kg nucleated cells and 1.4 +/- 2.7 x 10(5)/kg CD8+ cells. Patients also received cyclosporine starting day -1. Engraftment occurred in 28 patients (97%), including three patients who received a non-TBI conditioning regimen. One patient receiving an unrelated transplant failed to engraft. Median time to ANC > 500 x 10(6)/L was 17 (12-23) days. Four of 20 patients receiving grafts from HLA-identical siblings (20%) developed acute GVHD grade > or = II. However, five of eight patients with grafts from alternative donors (63%) had grade > or = II GVHD. Nearly all patients developed fever around day 7, accompanied by fluid overload, mild skin rash and shortness of breath. This syndrome necessitated treatment with steroids. Immunomagnetic CD8 depletion is a simple and reproducible method of selective T cell depletion. In combination with cyclosporine it appears to be effective in the prevention of severe acute GVHD in HLA-identical sibling transplants, but not in transplants from less perfectly matched donors.

Adult↗
PubMed1992

Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia.

Although rare cells expressing the bcr/abl fusion transcript can be detected by the polymerase chain reaction (PCR) in patient blood or marrow after allogeneic bone marrow transplant (BMT) for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukemia (CML), the prognostic significance of this finding is unknown. This paper reports clinical, cytogenetic, and molecular data derived from 64 CML patients following allogeneic BMT. Nested primer PCR was performed on patient blood and bone marrow samples to detect the presence of residual bcr/abl (+) cells in CML patients considered to be in clinical remission at the time of study. Bcr/abl transcripts were detected in 37 of 64 patients for at least one timepoint post-BMT. Thirteen of these 37 bcr/abl (+) patients have subsequently relapsed, as defined by clinical and/or persistent cytogenetic findings, in contrast to 0 relapses among the 27 bcr/abl (-) patients (P = .0025). The median time from first (+) bcr/abl PCR signal to relapse was 150 days (range 90 to 832). Fifty-four patients were studied at two or more timepoints post-BMT: five of eight patients persistently bcr/abl (+) have relapsed; 5 of 23 patients with both bcr/abl (+) and (-) assays during follow-up have relapsed; and none of 23 patients persistently (-) have relapsed (cumulative actuarial relapse rates 77%, 20%, and 0%, respectively, P = .0017). These data indicate that among CML patients in apparent clinical remission after BMT, nested primer bcr/abl PCR can define subgroups with low, intermediate, and high risk of relapse. The pattern of bcr/abl PCR detection after transplant may aid in the development of trials designed to reduce the risk of relapse, or allow for early intervention in patients who fail to clear the malignant clone.

Base Sequence↗
PubMed1992

The predictive value of HLA-DR oligotyping for MLC responses.

Comparison of HLA proteins between a patient and potential unrelated marrow donors is difficult because many similar, but not identical, HLA proteins are expressed in the human population. A reliable and practical method to detect these subtle differences is provided by oligotyping, a new technique that identifies polymorphic sequences in the genes encoding the HLA proteins. Oligotyping was used to compare polymorphic HLA-DR sequences in 286 pairs of samples from patients and potential unrelated donors who were serologically matched for HLA-DR specificities. Oligotyping detected HLA-DR differences in 53% of these pairs and all mismatched pairs were reactive in primary mixed lymphocyte cultures. Where HLA-DR disparity was not detected by oligotyping, 37% of the pairs were nonreactive in MLC. The remaining 63% often contained an allele associated with the HLA-DRw11 serological specificity. In the absence of HLA-DRB1*11, oligotyping was predictive of MLC reactivity for samples with HLA-DR2, -DR4, and DRw52. In clinical settings, the ability to predict MLC reactivity on the basis of precise HLA typing provides an alternative to MLC. Further, the relationship between specific polymorphic sequences and reactivity in MLC may lead to more fundamental insights into the mechanisms involved in alloreactive responses.

Amino Acid Sequence↗
PubMed1990

Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases.

From April, 1985, to February, 1989, 102 consecutive patients received unrelated donor bone marrow transplantation therapy for chronic myelogenous leukemia (CML) at four centers. Median age of the group was 31 years (range, 4.5 to 51 years). Fifty-four patients were in first chronic phase (CP) at time of transplantation, and 48 had evidence of more advanced disease (AD) (accelerated phase, 32; blast crisis, 9; second CP, 7). In 44 cases, the donor and recipient were identical at the HLA A, B, and DR loci and were nonreactive in bidirectional mixed leukocyte culture (MLC) ("matched"). In 58 cases, nonidentity between donor and recipient could be determined at at least one HLA locus or in bidirectional MLC ("mismatched"). Fifty-eight patients were prepared for transplantation with a combination of cyclophosphamide and fractionated total body irradiation (FTBI) and received acute graft-versus-host disease (GVHD) prophylaxis consisting of methotrexate alone or in combination with cyclosporine, prednisone, or antithymocyte globulin (ATG). In 44 cases, patients received preparative agents in addition to cyclophosphamide and FTBI, and marrow depleted of mature T lymphocytes by ex vivo incubation with either anti-CD3 antibody plus complement (n = 24) or Campath-1 (n = 20). Engraftment defined by a peripheral blood neutrophil count greater than 0.5 X 10(9)/L was demonstrated in 92 cases and occurred at a median of 22 days (range, 11 to 46 days). In 10 cases, peripheral blood evidence of engraftment did not occur, and in one case, engraftment was followed by aplasia. Hematologic relapse was seen in four cases. Recurrence or persistence of the Ph1 chromosome without evidence of hematologic relapse occurred in four additional cases. The incidence of grade II to IV acute GVHD is 65% (95% confidence interval [CI], +/- 10%). After adjustment for recipient age and donor matching status, recipients of T lymphocyte-depleted donor marrow had a significantly lower incidence of grade II to IV acute GVHD (P less than .01); however, T depletion was not significantly associated with improved survival (P = .34), disease-free survival (P = .51), or increased incidence of relapse (P = .39). Of 102 patients, 46 are alive, with a median survival of 12 months (range, 3 to 46 months), and the Kaplan-Meier estimate of disease-free survival is 29% (95% CI, +/- 9%) for the entire group at 2 1/2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1989

Bone marrow transplantation for children with severe aplastic anemia: use of donors other than HLA-identical siblings.

Eighty-five percent of untransfused and 70% of transfused patients with severe aplastic anemia (SAA) are cured with bone marrow transplants from histocompatible sibling donors. Use of partially matched family donors or unrelated donors has been relatively unsuccessful because of high incidences of graft rejection and graft-versus-host disease (GVHD). Thirteen children with SAA received marrow grafts from alternative donors (sibling 4, parent 5, unrelated 4). The first three patients were pretreated with cyclophosphamide (CYCLO) +/- irradiation and received methotrexate for GVHD prophylaxis. Subsequent children were pretreated with CYCLO + high-dose cytosine arabinoside + methylprednisolone + total body irradiation, had monoclonal antibody T-cell depletion of the donor marrow, and received cyclosporine for GVHD prophylaxis. Three heavily transfused patients with haploidentical-related donors failed to engraft and died. All 10 patients with more closely matched donors engrafted. Acute GVHD was grade II in only one patient (non-T-depleted); this patient is the only one with severe chronic GVHD. Three engrafted patients died (Pneumocystis pneumonia, systemic parainfluenza, venocclusive disease). Seven children are alive 33+ to 2,692+ days. Donors for the survivors were siblings 3, parent 1, unrelated 3. These data suggest that bone marrow transplantation from closely matched donors other than histocompatible siblings can be effective therapy for SAA if an intensive conditioning regimen is used. These results must be confirmed with larger numbers and longer follow-up.

Adolescent↗
PubMed1989

The use of unrelated bone marrow donors in the treatment of patients with chronic myelogenous leukemia: experience of four marrow transplant centers.

Thirty-seven patients with chronic myelogenous leukemia who lacked an HLA-identical sibling were transplanted with bone marrow from an HLA-A,B,DR-matched, one locus-mismatched, or two locus-mismatched unrelated volunteer donor. Twenty-two were in chronic phase and 15 had advanced to either accelerated phase or blast crisis. The projected 1000-day survival is 55% for chronic phase patients and 22% for accelerated or blast phase patients. For patients transplanted during chronic phase, results appeared to be comparable whether the donor was fully HLA-matched or HLA one locus-mismatched. These results indicate that marrow grafting from either HLA-identical or HLA one locus-mismatched volunteer donors may be effective therapy for patients with chronic myelogenous leukemia who lack an acceptable related donor.

Adolescent↗
PubMed1988

Partially matched bone marrow transplantation in patients with myelodysplastic syndromes.

Six patients with a myelodysplastic syndrome (MDS) were treated with bone marrow transplantation (BMT) using partially-matched related (3) or unrelated (3) donors. Patients' ages ranged from 7 to 31 years (median, 10 years). Bone marrow karyotype abnormalities were present in five patients included four with monosomy 7 and one with trisomy 8. One patient was in complete remission before transplant; the remaining five had excess of blasts or were undergoing leukemic transformation. Donor, and recipient were mismatched at the DR locus (2), A locus (2), B locus (1), or A and B loci (1). Conditioning included busulfan, cytarabine, cyclophosphamide, methylprednisolone, and total body irradiation. Cyclosporine was started on day -1. Marrows were T-cell depleted using a monoclonal antibody (MoAb) (CD3) and normal rabbit serum. Four patients engrafted routinely. One patient died of aspergillosis before engraftment (day 12) and one patient failed to engraft on first attempt, but engrafted following additional preparation. Median time to neutrophils greater than 500/microL and platelets greater than 25,000/microL were 16 and 19 days, respectively. Acute graft-v-host disease (GVHD) was less than or equal to grade II in all patients. One patient died with recurrent disease (day 257). One patient died at day 515 of pancreatitis and respiratory failure. Three patients are alive and disease-free at 240, 395, and 560 days post-BMT including two patients with unrelated donors. Partially matched T-depleted bone marrow from related or unrelated donors may be effective, and possibly curative therapy for patients with MDS who lack a histocompatibility locus antigen (HLA)-identical sibling donor.

Adolescent↗
PubMed1987

The time-course of appearance and net accumulation of horseradish peroxidase (HRP) presented orally to rainbow trout Salmo gairdneri (Richardson).

1. A sensitive enzyme-linked immunosorbent assay (ELISA) technique was used in order to determine horseradish peroxidase (HRP) uptake from the rainbow trout gut. 2. HRP was detected in blood plasma and various tissues within 15 min of oral intubation. 3. The time-course of net accumulation (uptake-degradation) over a 75 min period was recorded. 4. The presence of HRP reached a maximum in the body tissues approximately 45 min after intubation and on a ng/g weight basis the order of accumulation within the tissues was liver greater than spleen = kidney greater than plasma greater than heart. 5. The total organ accumulation (net) was in the order liver greater than plasma greater than kidney greater than spleen greater than heart.

Animals↗
PubMed1986

The time-course of appearance and net accumulation of horseradish peroxidase (HRP) presented orally to juvenile carp Cyprinus carpio (L.).

A sensitive enzyme-linked immunosorbent assay (ELISA) technique was used in order to determine horseradish peroxidase (HRP) uptake from the carp gut. HRP was detected in blood plasma and various tissues within 15 min of oral intubation. The time-course of net accumulation (uptake-degradation) over a 2 hr period was recorded. The presence of HRP reached a maximum in the body tissues approximately 1 hr after intubation and on a microgram/g wet weight basis the order of accumulation within the tissues was spleen greater than kidney greater than liver. The total organ accumulation (net) was in the order liver greater than kidney greater than spleen.

Administration, Oral↗
PubMed1986

Aleukemic leukemia cutis.

A 46-year-old man presented with nodular skin lesions, a biopsy specimen of which demonstrated a poorly differentiated malignancy. Touch preparations with histochemical staining and electron microscopy confirmed leukemia cutis. Results from a bone marrow aspirate disclosed focal areas of increased myeloblasts, and cytogenetic analysis revealed an abnormal karyotype as follows 46,XY, t(1;2) (q44p13). Antileukemic therapy resulted in prompt disappearance of the skin nodules, and a return of the patient's bone marrow to normal was noted, but after six months of intensive chemotherapy leukemia cutis recurred without morphologically identifiable leukemia in the bone marrow. The patient underwent successful bone marrow transplantation from an HLA-identical sibling but died 70 days after the transplant from disseminated aspergillosis.

Acute Disease↗