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Biomedical subjects

D Reardon

Publications and source records attributed to D Reardon.

At least 19 recordsLinked to original sources
PubMed2001

High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome.

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with >or= 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150-775 mg/m(2)infused over 24 hours, doxorubicin 165 mg/m(2)as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg(-1). There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m(2) dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan-Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51-83%) and 77% (95% CI; 64-93%). Paclitaxel up to 725 mg/m(2) infused over 24 hours in combination with with doxorubicin 165 mg/m(2) and cyclophosphamide 100 mg kg(-1) is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing.

Adult↗
PubMed2001

The relative role of ErbB1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells.

Activation of the epidermal growth receptor (ErbB1) occurs within minutes of a radiation exposure. Immediate downstream consequences of this activation are currently indistinguishable from those obtained with growth factors (GF), e.g. stimulation of the pro-proliferative mitogen-activated protein kinase (MAPK). To identify potential differences, the effects of GFs and radiation on other members of the ErbB family have been compared in mammary carcinoma cell lines differing in their ErbB expression profiles. Treatment of cells with EGF (ErbB1-specific) or heregulin (ErbB4-specific) resulted in a hierarchic transactivations of ErbB2 and ErbB3 dependent on GF binding specificity. In contrast, radiation indiscriminately activated all ErbB species with the activation profile reflecting that cell's ErbB expression profile. Downstream consequences of these ErbB interactions were examined with MAPK after specifically inhibiting ErbB1 (or 4) with tyrphostin AG1478 or ErbB2 with tyrphostin AG825. MAPK activation by GFs or radiation was completely inhibited by AG1478 indicating total dependance on ErbB1 (or 4) depending on which ErbB is expressed. Inhibiting ErbB2 caused an enhanced MAPK response simulating an amplified ErbB1 (or 4) response. Thus ErbB2 is a modulator of ErbB1 (or 4) function leading to different MAPK response profiles to GF or radiation exposure.

Autocrine Communication↗
PubMed2001

Tandem-cycle high-dose melphalan and cisplatin with peripheral blood progenitor cell support in patients with breast cancer and other malignancies.

We evaluated the feasibility of tandem-cycle high-dose chemotherapy (HDCT) with cisplatin, melphalan, and peripheral blood progenitor cells (PBPCs). Fifty patients with high-risk primary (n = 17) or stage IV breast cancer (n = 29) or other malignancies (n = 4) received 2 cycles of intravenous melphalan, 20 to 151.8 mg/m2, and cisplatin, 200 mg/m2, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF. Starting at 40 mg/m2 of melphalan, patients also received PBPCs. Delayed platelet recovery defined the maximum tolerated dose (MTD) for melphalan at 101.2 mg/m2 per cycle. There were no treatment-related deaths. Cycle 2 was delivered at a median of 1.7 months after cycle 1; 72% of patients treated at the MTD received both cycles. Cycle 2 was omitted when patients refused it or had disease progression or toxicities, primarily prolonged thrombocytopenia. Complete response rates in stage IV breast cancer patients increased from 28% pre-HDCT to 55% after cycle 2. At a median follow-up of 4.6 years (range, 1.5-8.1 years), 11 of 29 patients with stage IV breast carcinoma were alive with 5-year projected progression-free and overall survival rates of 19% (95% confidence interval [CI], 7%-41%) and 39% (95% CI, 20%-62%), respectively. Five-year projected progression-free and overall survival rates for patients with stage IV breast cancer in complete response following HDCT versus all others were 35% (95% CI, 15%-70%) versus 0% (P = .01) and 61% (95% CI, 35%-91%) versus 10% (95% CI, 2%-60%) (P = .003; log-rank test), respectively. Estrogen-receptor positivity was predictive of reduced risk of progression (relative risk [RR], 0.25; 95% CI, 0.10-0.65; P = .003) and death (RR, 0.27; 95% CI, 0.10-0.72; P = .009) after adjusting for response status. Five-year projected relapse-free and overall survival rates were 71% (95% CI, 43%-96%) and 82% (95% CI, 56%-100%), respectively, for the 17 patients with high-risk primary breast cancer. Tandem-cycle high-dose melphalan and cisplatin with PBPCs is feasible. Preliminary data suggest significant activity in selected patients with stage IV responding breast carcinoma.

Adult↗
PubMed2000

Identification of PATCHED mutations in medulloblastomas by direct sequencing.

Medulloblastoma is the most common malignant embryonic tumors of the central nervous system. The nevoid basal cell carcinoma syndrome (NBCCS), which is caused by mutations of PTCH gene on chromosome 9q22, accounts for about 2% of all medulloblastomas. Previous studies of PTCH in sporadic medulloblastomas using single strand conformational polymorphism (SSCP) detected mutations in about 10% of the tumors. In this study, we directly sequenced the PTCH gene in 20 sporadic medulloblastoma DNA samples. A nonsense mutation (Q694X) and a splice site alteration (2875+1G>A) were identified in two of the samples. The mutations are predicted to result in a truncated PTCH protein and aberrant splicing, respectively. In both cases, only the mutant alleles were identified, indicating that the mutations were associated with loss of the wild-type PTCH allele in the tumor cells. Several novel variants, including 1653T>C, 1672C>T, and 2292C>T, were also found in these tumor samples. One of the two mutations detected in this study had been missed by SSCP, suggesting that the true rate of PTCH mutations in sporadic medulloblastomas may be underestimated by SSCP screening. Nevertheless, the frequency of mutations in this study did not differ from previous reports.

Cerebellar Neoplasms↗
PubMed2000

The vitamin D3 analog EB 1089 enhances the antiproliferative and apoptotic effects of adriamycin in MCF-7 breast tumor cells.

Exposure of MCF-7 breast tumor cells to the vitamin D3 analog, EB 1089 enhances the response to adriamycin. Clonogenic survival studies indicate that EB 1089 shifts the dose-response curve for sensitivity to adriamycin by approximately six-fold in p53 wild-type MCF-7 cells; comparative studies in MCF-7 cells with a temperature-sensitive dominant negative p53 mutation show less than a two-fold shift in adriamycin sensitivity in the presence of EB 1089. The combination of EB 1089 with adriamycin also promotes apoptotic cell death in the p53 wild-type MCF-7 cells but not in the MCF-7 cells expressing mutant p53. EB 1089 treatment blocks the increase in p21waf1/cip1 levels induced by adriamycin and interferes with induction of MAP kinase activity by ionizing radiation, effects which could be related to the capacity of EB 1089 to promote secretion of insulin-like growth factor binding protein. Taken together with our previous findings that EB 1089 enhances breast tumor cell sensitivity to ionizing radiation, there studies further support the concept that vitamin D3 analogs could have utility in combination with conventional chemotherapy and/or radiotherapy in the treatment of breast cancer.

Anti-Bacterial Agents↗
PubMed1999

Folding of an isolated ribonuclease H core fragment.

Based on results from both equilibrium and kinetic hydrogen exchange studies of Escherichia coli ribonuclease HI (RNase H), a fragment of RNase H (eABCD) was designed. The sequence of eABCD contains less than half of the protein's primary sequence and includes the regions that were shown to be the most protected from hydrogen exchange in all previous studies of RNase H. This core fragment of RNase H encodes a well-ordered protein with native-like properties. When isolated from the full-length monomeric protein, the eABCD fragment forms a stable dimer. However, we show indirectly that the monomeric form of eABCD is folded and has an overall secondary structure similar to the dimeric form.

Circular Dichroism↗
PubMed1999

Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital.

PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% +/- 10%. The 5-year progression-free survival rate was 21% +/- 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of -3.9 intelligence quotient points per year (P =.0028). Sensory functions declined significantly after therapy (P =.007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.

Age Factors↗
PubMed1998

MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's disease in children: results of the Children's Cancer Group Phase III Trial.

PURPOSE: A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990. PATIENTS AND METHODS: One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease. RESULTS: Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting. CONCLUSION: The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.

Adolescent↗
PubMed1995

Human type I interferon receptor, IFNAR, is a heavily glycosylated 120-130 kD membrane protein.

Type I interferons (IFNs) bind and signal through cell surface receptors that share at least one common component. One candidate for such a component is the interferon-alpha receptor (IFNAR). Genetic studies have shown that the IFNAR gene product is required for response to many type I interferons. However, these studies also suggest that the IFNAR protein interacts with an additional receptor component(s) to form functionally complete type I IFN receptors. Although these genetic studies have contributed significantly to understanding the type I IFN receptors. Although these genetic studies have contributed significantly to understanding the type I IFN receptors, little biochemical characterization of IFNAR and its function has been reported. To facilitate biochemical studies of the IFNAR gene product, a monoclonal antibody, GB8, recognizing the extracellular domain of IFNAR was prepared. The epitope for GB8 maps to the second extracellular domain of IFNAR between amino acids 278 and 293. GB8 identifies IFNAR in western blots of cell membranes as a broad band with molecular mass ranging from 100 to 150 kD in membranes from CHO cells overexpressing the human IFNAR gene to 136-150 kD in Daudi cell membranes. Such variations in the mean value and the range of molecular mass between IFNAR in different cell lines suggest differences in glycosylation. The majority of glycosylation is N-linked, although there may also be a small amount O-linked oligosaccharide. Deglycosylation of IFNAR in Daudi cell membranes results in a 70 kD IFNAR species, indicating that nearly half of the apparent molecular mass of Daudi cell IFNAR is contributed by carbohydrate moieties.

Amino Acid Sequence↗
PubMed1995

The structure and evolution of alpha/beta barrel proteins.

Roughly 10% of all known enzyme structures have an alpha/beta barrel domain. The members of this large family of proteins catalyze very different types of reactions. Such diversity of function has made this family a target for protein engineering. The evolutionary history of this family has been the subject of vigorous debate. In this paper, arguments are made to support the divergence of all members of this family from a common ancestor. Because of the lack of strong sequence homology, the ancestral molecule must be very old. A hypothesis concerning the relationship between chemical mechanism and evolutionary history is discussed. Evidence is presented to suggest that convergent molecular evolution occurs when there is only one energetically reasonable pathway for a chemical reaction.

Amino Acid Sequence↗
PubMed1992

Differential impact of abortion on adolescents and adults.

The purpose of this study was to compare adolescent and adult reactions to abortion. A sample of 252 women from 42 states was obtained from a national survey of organizations serving as support groups for women who have had negative reactions to abortion. The age analysis was run using t-tests. Results indicated that the adolescents were significantly more likely to be dissatisfied with the choice of abortion than were the older subjects, to have abortions later in the gestational period, to be dissatisfied with services at the time of the abortion, to feel forced by circumstances to have the abortion, to report being misinformed at the time of the abortion, and to report greater severity of psychological stress. The conclusions suggest that the adolescents' problems may be due to a combination of developmental limitations and the nature of counseling at the time of the abortion.

Abortion Applicants↗
PubMed1990

The size and number of bone marrow megakaryocytes in malignant lymphoma and their relationship to abnormalities in platelet count.

Platelet counts were measured routinely in 718 volunteer blood donors and 124 patients with malignant lymphoma. When considered by gender, the mean platelet counts of the patients with malignant lymphoma were significantly increased when compared to controls (P less than 0.01). In addition, 9% of males and 4% of females with lymphoma exhibited a thrombocytosis, in which their platelet counts exceeded the upper limit of the normal platelet count for control subjects (defined as 2 SDs in excess of the mean value). Megakaryocyte whole size, cytoplasmic and nuclear sizes, and megakaryocyte numbers were also quantified in bone marrow obtained from the iliac crest of 5 hematologically normal subjects and 26 patients with malignant lymphoma. Mean megakaryocyte sizes were significantly greater in subjects with lymphoma, when compared to control values (P less than 0.05). No significant differences in megakaryocyte numbers in bone marrow were observed between the two groups. For subjects with malignant lymphoma, platelet count was found to be significantly positively correlated with megakaryocyte size. The results of this study suggest that the elevated platelet count associated with malignant lymphoma is mediated by an increase in the size of the megakaryocytes in the bone marrow.

Adolescent↗
PubMed1989

Coagulation changes following hepatic revascularization during liver transplantation.

The coagulation changes during liver transplantation have been studied in 14 selected patients. Blood usage in all cases was limited to 8.5 liters, and the preoperative coagulation results were only minimally deranged. Bleeding during the operative procedure was easily managed in all cases. Nonetheless, even in this selected group of "low risk" patients, we have demonstrated that during the anhepatic phase and particularly following hepatic revascularization there is activation of both coagulation and fibrinolysis. These findings imply that if bleeding occurs following revascularization, in addition to the use of replacement blood products, treatment should be directed at reducing the consumptive coagulopathy and inhibiting fibrinolysis. We suggest as a first step antithrombin supplementation to maintain activity above 70%, and an antifibrinolytic agent, such as aprotonin, should be considered as adjuncts to therapy at revascularization.

Age Factors↗
PubMed1989

Rapid diagnosis of leukaemia: a three-stage immunophenotyping technique.

We have developed a three-stage avidin-biotin alkaline phosphatase system (ABAP) for immunophenotyping acute and chronic leukaemias. Air-dried blood and bone marrow films or cytospins were fixed in acetone, methanol-acetone, or methanol-acetone-formalin. A primary monoclonal antibody layer was employed with a corresponding biotinylated anti-species second layer. The third stage was avidin-conjugated alkaline phosphatase and visualisation was achieved with Fast Red TR as diazo salt. This was compared using a limited range of primary antibodies with the alkaline phosphatase anti-alkaline phosphatase (APAAP) method, routinely performed as a five-stage technique. The ABAP technique provided a 2.5 h, reliable, three-stage immunophenotyping procedure without the need for amplification steps. A wider range of first layer monoclonals of any species could be utilised by using the appropriate secondary antibody. Preservation of cell morphology was very good. Smaller amounts of expensive monoclonal antibodies could be used compared to the quantity required with other slide techniques. This approach to immunophenotyping can consequently be employed by any general haematology laboratory to provide a sensitive and inexpensive service. The technique has been in routine diagnostic use for the last 2 years, and consistently good results have so far been achieved in a national external immunophenotyping quality assurance scheme.

Acute Disease↗
PubMed1988

Changes in factor VIII proteins after cardiopulmonary bypass in man suggest endothelial damage.

16 patients undergoing coronary artery bypass grafting using cardiopulmonary bypass (CPB) had blood samples taken at various times before, during and up to 1 week after surgery for estimation of beta-thromboglobulin (BTG), alpha-1-antichymotrypsin (ACT), factor VIII procoagulant protein (VIII:C), von Willebrand factor antigen (vWF:Ag) and ristocetin co-factor (vWF:RiCoF). vWF:Ag and vWF:RiCoF rose during and following surgery in a different manner to ACT. At 1 week there was a significantly disproportionate rise in vWF:Ag compared to vWF:RiCoF which suggested a degree of pulmonary endothelial damage. Prostacyclin, which was administered to 8 of the patients during CPB, reduced platelet activation as measured by a reduction in the release of BTG and also attenuated the consumption of VIII:C. It had no effect on pulmonary endothelial damage as measured by the ratio of vWF:Ag to vWF:RiCoF.

Adult↗