Biomedical subjects

Peter J Shaw

Publications and source records attributed to Peter J Shaw.

At least 19 recordsLinked to original sources

PubMed2006

Plasma protein distribution and its impact on pharmacokinetics of liposomal amphotericin B in paediatric patients with malignant diseases.

OBJECTIVE: This study investigates the association of liposomal amphotericin B (L-AmB) with plasma proteins and its impact on the pharmacokinetics of L-AmB in paediatric patients with malignant diseases. METHODS: Paediatric oncology patients (n = 39) who received multiple-doses of L-AmB were recruited into this study. The association of the drug with plasma lipoprotein was investigated using single vertical spin density gradient ultracentrifugation and quantitated with a validated HPLC assay. The unbound amphotericin B (AmB) in the plasma was separated by ultrafiltration and determined with a validated LC/MS/MS assay. RESULTS: The ex vivo lipoprotein distribution of L-AmB found that 68.3 +/- 11.8% of the drug was associated with the high density lipoprotein (HDL) fraction, which demonstrated a significant inverse correlation with posterior Bayesian estimates of L-AmB clearance (r = -0.690, p < 0.01). The average of unbound fraction of AmB in plasma of patients administered with L-AmB was 0.005, but its relationship with L-AmB clearance did not reach a statistical significance. CONCLUSION: L-AmB displays different lipoprotein distribution profile from that of the conventional AmB formulation, with L-AmB preferentially associated with HDL in plasma. The inverse correlation of L-AmB clearance to its HDL distribution contributes to the difference in the pharmacokinetic profile of L-AmB.

Amphotericin B↗

PubMed2006

Structure and function of the nucleolus in the spotlight.

The nucleolus is the most obvious and clearly differentiated nuclear sub-compartment. It is where ribosome biogenesis takes place, but it is becoming clear that the nucleolus also has non-ribosomal functions. In this review we discuss recent progress in our understanding of how both ribosome biosynthesis and some non-ribosomal functions relate to observable nucleolar structure. We still do not have detailed enough information about the in situ organization of the various processes taking place in the nucleolus. However, the present power of light and electron microscopy techniques means that a description of the organization of nucleolar processes at the molecular level is now achievable, and the time is ripe for such an effort.

Animals↗

PubMed2006

Expansion of functionally immature transitional B cells is associated with human-immunodeficient states characterized by impaired humoral immunity.

X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency associated with a marked reduction in circulating memory B cells. Our investigation of the B cell compartment of XLP patients revealed an increase in the frequency of a population of B cells distinct from those previously defined. This population displayed increased expression of CD10, CD24, and CD38, indicating that it could consist of circulating immature/transitional B cells. Supporting this possibility, CD10+CD24highCD38high B cells displayed other immature characteristics, including unmutated Ig V genes and elevated levels of surface IgM; they also lacked expression of Bcl-2 and a panel of activation molecules. The capacity of CD24highCD38high B cells to proliferate, secrete Ig, and migrate in vitro was greatly reduced compared with mature B cell populations. Moreover, CD24highCD38high B cells were increased in the peripheral blood of neonates, patients with common variable immunodeficiency, and patients recovering from hemopoietic stem cell transplant. Thus, an expansion of functionally immature B cells may contribute to the humoral immunodeficient state that is characteristic of neonates, as well as patients with XLP or common variable immunodeficiency, and those recovering from a stem cell transplant. Further investigation of transitional B cells will improve our understanding of human B cell development and how alterations to this process may precipitate immunodeficiency or autoimmunity.

ADP-ribosyl Cyclase 1↗

PubMed2006

Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive Hodgkin's lymphoma.

PURPOSE: Latent Epstein-Barr virus (EBV) genomes are found in the malignant cells of approximately one-third of Hodgkin's lymphoma (HL) cases. Detection and quantitation of EBV viral DNA could potentially be used as a biomarker of disease activity. EXPERIMENTAL DESIGN: Initially, EBV-DNA viral load was prospectively monitored from peripheral blood mononuclear cells (PBMC) in patients with HL. Subsequently, we analyzed viral load in plasma from a second cohort of patients. A total of 58 patients with HL (31 newly diagnosed, 6 relapsed, and 21 in long-term remission) were tested. Using real-time PCR, 43 PBMC and 52 plasma samples were analyzed. RESULTS: EBV-DNA was detectable in the plasma of all EBV-positive patients with HL prior to therapy. However, viral DNA was undetectable following therapy in responding patients (P = 0.0156), EBV-positive HL patients in long-term remission (P = 0.0011), and in all patients with EBV-negative HL (P = 0.0238). Conversely, there was no association seen for the EBV-DNA load measured from PBMC in patients with active EBV-positive HL patients as compared with EBV-negative HL, or patients in long-term remission. EBV-DNA load in matched plasma/PBMC samples were not correlated. CONCLUSIONS: We show that free plasma EBV-DNA has excellent sensitivity and specificity, and can be used as a noninvasive biomarker for EBV-positive HL and that serial monitoring could predict response to therapy. Additional prospective studies are required to further evaluate the use of free plasma EBV-DNA as a biomarker for monitoring response to treatment in patients with EBV-positive HL.

Adolescent↗

PubMed2006

Allogeneic bone marrow transplantation with reduced intensity conditioning for chronic granulomatous disease complicated by invasive Aspergillus infection.

Chronic granulomatous disease (CGD) is a rare disorder characterized by recurrent infections, often resulting in impaired quality of life and death. Allogeneic BMT provides a definitive cure for CGD, but carries a significant risk of mortality and morbidity. The risk is higher for those who have invasive fungal infection prior to transplant. Reduced intensity conditioning (RIC) is associated with less toxicity from the conditioning agents and may provide an alternative option for all non-malignant diseases. We report a case of successful allogeneic BMT after RIC for a case of X-linked CGD complicated by severe invasive aspergillosis (IA).

Antifungal Agents↗

PubMed2006

New insights into nucleolar architecture and activity.

The nucleolus is the most obvious and clearly differentiated nuclear subcompartment. It is where ribosome biogenesis takes place and has been the subject of research over many decades. In recent years progress in our understanding of ribosome biogenesis has been rapid and is accelerating. This review discusses current understanding of how the biochemical processes of ribosome biosynthesis relate to an observable nucleolar structure. Emerging evidence is also described that points to other, unconventional roles for the nucleolus, particularly in the biogenesis of other RNA-containing cellular machinery, and in stress sensing and the control of cellular activity. Striking recent observations show that the nucleolus and its components are highly dynamic, and that the steady state structure observed by microscopical methods must be interpreted as the product of these dynamic processes. We still do not have detailed enough information to understand fully the organization and regulation of the various processes taking place in the nucleolus. However, the present power of light and electron microscopy (EM) techniques means that a description of nucleolar processes at the molecular level is now achievable, and the time is ripe for such an effort.

Animals↗

PubMed2006

Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases.

A population pharmacokinetic model of liposomal amphotericin B (L-AmB) in pediatric patients with malignant diseases was developed and evaluated. Blood samples were collected from 39 pediatric oncology patients who received multiple doses of L-AmB with a dose range from 0.8 to 5.9 mg/kg of body weight/day. The patient cohort had an average age of 7 years (range, 0.2 to 17 years) and weighed an average of 28.8 +/- 19.8 kg. Population pharmacokinetic analyses were performed with NONMEM software. Pharmacokinetic parameters, interindividual variability (IIV), between-occasion variability (BOV), and intraindividual variability were estimated. The influence of patient characteristics on the pharmacokinetics of L-AmB was explored. The final population pharmacokinetic model was evaluated by using a bootstrap sampling technique. The L-AmB plasma concentration-time data was described by a two-compartment pharmacokinetic model with zero-order input and first-order elimination. The population mean estimates of clearance (CL) and volume of distribution in the central compartment (V1) were 0.44 liters/h and 3.12 liters, respectively, and exhibited IIV (CL, 10%) and significant BOV (CL, 46% and V1, 56%). The covariate models were CL (liters/h) = 0.44 . e(0.0152.(WT-21)) and V1 (liters) = 3.12.e(0.0241.(WT-21)), where WT is the patient's body weight (kg) centered on the study population cohort median of 21 kg. Model evaluation by the bootstrap procedure indicated that the full pharmacokinetic model was robust and parameter estimates were accurate. In conclusion, the pharmacokinetics of L-AmB in pediatric oncology patients were adequately described by the developed population model. The model has been evaluated and can be used in the design of rational dosing strategies for L-AmB antifungal therapy in this special population.

Adolescent↗

PubMed2005

Arabidopsis nucleolar protein database (AtNoPDB).

The Arabidopsis Nucleolar Protein Database (http://bioinf.scri.sari.ac.uk/cgi-bin/atnopdb/home) provides information on 217 proteins identified in a proteomic analysis of nucleoli isolated from Arabidopsis cell culture. The database is organized on the basis of the Arabidopsis gene identifier number. The information provided includes protein description, protein class, whether or not the plant protein has a homologue in the most recent human nucleolar proteome and the results of reciprocal BLAST analysis of the human proteome. In addition, for one-third of the 217 Arabidopsis nucleolar proteins, localization images are available from analysis of full-length cDNA-green fluorescent protein (GFP) fusions and the strength of signal in different parts of the cell-nucleolus, nucleolus-associated structures, nucleoplasm, nuclear bodies and extra-nuclear-is provided. For each protein, the most likely human and yeast orthologues, where identifiable through BLASTX analysis, are given with links to relevant information sources.

Arabidopsis Proteins↗

PubMed2005

Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation.

AIM: To analyse the pharmacokinetics of melphalan in 52 children (0.3-18 years) and determine whether any clinical factors affect the pharmacokinetic parameters Additionally, to examine whether a test melphalan dose can predict the pharmacokinetics of a full dose, when there are 5 intervening days of carboplatin therapy. METHODS: Melphalan concentrations were measured in 14 blood samples collected from each child following doses ranging from 30 to 180 mg m(-2). The pharmacokinetics were analysed with Kinetica 4.0. RESULTS: Children who did not have carboplatin (n = 27) had median melphalan clearance (CL) of 15.5 l h(-1) m(-2) (interquartile range: 12.4-19.9 l h(-1) m(-2)) and steady state volume of distribution (Vss) of 14.9 l m(-2) (interquartile range: 12.7-18.3 l m(-2)). Children who had carboplatin (n = 25) had 34% lower median CL (10.2 l h(-1) m(-2)) and 18% lower median Vss (12.2 l m(-2)) (P < 0.001). Melphalan elimination was impaired in a separate group of three children given concomitant carboplatin and etoposide. Stepwise multiple linear regression indicated that weight, carboplatin, glomerular filtration rate (GFR) and total body irradiation (TBI) significantly affected CL, while weight and carboplatin influenced Vss. A test dose (10 mg m(-2)) tended to underpredict the area-under-the-concentration-vs.-time-curve for a full (180 mg m(-2)) dose in 19 individuals given carboplatin. CONCLUSIONS: In children, melphalan CL is influenced by weight, carboplatin, TBI and GFR. Vss is influenced by weight and carboplatin.

Adolescent↗

PubMed2004

Proteomic analysis of the Arabidopsis nucleolus suggests novel nucleolar functions.

The eukaryotic nucleolus is involved in ribosome biogenesis and a wide range of other RNA metabolism and cellular functions. An important step in the functional analysis of the nucleolus is to determine the complement of proteins of this nuclear compartment. Here, we describe the first proteomic analysis of plant (Arabidopsis thaliana) nucleoli, in which we have identified 217 proteins. This allows a direct comparison of the proteomes of an important nuclear structure between two widely divergent species: human and Arabidopsis. The comparison identified many common proteins, plant-specific proteins, proteins of unknown function found in both proteomes, and proteins that were nucleolar in plants but nonnucleolar in human. Seventy-two proteins were expressed as GFP fusions and 87% showed nucleolar or nucleolar-associated localization. In a striking and unexpected finding, we have identified six components of the postsplicing exon-junction complex (EJC) involved in mRNA export and nonsense-mediated decay (NMD)/mRNA surveillance. This association was confirmed by GFP-fusion protein localization. These results raise the possibility that in plants, nucleoli may have additional functions in mRNA export or surveillance.

Arabidopsis↗

PubMed2004

Role of hydrochloric acid in the treatment of central venous catheter infections in children with cancer.

BACKGROUND: The use of central venous catheters (CVCs) in pediatric cancer patients is associated with substantial risk of producing sepsis. The treatment of catheter-related infections has generally consisted of antibiotic administration with or without catheter removal. The authors report the first published experience using intraluminal hydrochloric acid (HCl) instillation as an adjunct to systemic antimicrobials in the management of catheter-related infections in children with cancer. METHODS: All episodes of intraluminal instillation of 2 M HCl in oncology patients at The Children's Hospital at Westmead between December 1994 and August 2000 were reviewed. Episodes of HCl use were identified from a prospectively maintained infection data base. Successful treatment was defined as no recurrence of infection and no need for CVC removal in the 100 days after HCl administration. RESULTS: Forty-two episodes of HCl instillation were evaluated that occurred in children in whom blood cultures remained positive despite 48 hours of appropriate, systemic antibiotics and formed the basis of this review. All patients had in situ a surgically placed, subcutaneously tunneled CVC. The combination of systemic antibiotic therapy and HCl instillation was successful in eradicating infection in 67% of infection episodes in this patient cohort. The catheter salvage rate was 83% in patients with isolated Gram-negative infections, 75% in patients with isolated fungemia, and 50% in patients with isolated Gram-positive infections. CONCLUSIONS: The results suggest that HCl instillation is a useful adjunct to systemic antibiotic therapy, enabling both catheter salvage and eradication of antibiotic-refractory catheter-related infection.

Anti-Infective Agents↗

PubMed2004

Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice.

OBJECTIVE: Optimizing cord blood donor selection based mainly on cell dose and human leukocyte antigen (HLA) disparities may further improve results of unrelated cord blood transplants (UCBT). MATERIALS AND RESULTS: We analyzed 550 UCBTs for hematologic malignancies reported to the Eurocord Registry. Main outcomes and prognostic factors were analyzed in univariable and multivariable analyses incorporating center and period effects and using death and relapse as competitive risks for nonfatal endpoints. Nucleated cell (NC) dose before freezing and number of HLA disparities had a significant influence on outcome. Cumulative incidence (CI) of neutrophil and platelet recovery was associated with the number of HLA mismatches, number of NC before freezing, and use of granulocyte colony-stimulating factor. Coexistence of HLA class I and II disparities and high CD34 cell dose in the graft were associated with graft-vs-host disease grades III-IV. CI of disease relapse was higher in matched transplants showing a graft-vs-leukemia effect increased in HLA-mismatched transplants. Overall 3-year survival was 34.4%. Prognostic factors for survival were recipient age, gender, and disease status. CONCLUSION: Our results provide indications for a better choice of cord blood units according to cord blood cell content and HLA.

Adolescent↗

PubMed2004

Plant nuclear bodies.

Knowledge of the organization of transcription, RNA processing and transport, and the assembly of complexes such as the ribosome, spliceosome and other RNPs is essential to understanding gene expression. Over several years, the nucleolus and Cajal bodies have been examined in plants, and recently, various other sub-nuclear domains that are involved in RNA metabolism and hormonal responses have been discovered. These novel domains illustrate the complexity and subtlety of expression control and herald a new era of research on the molecular and cell biology of plant nuclei.

Animals↗

PubMed2003

Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis.

Results of unrelated cord blood transplantation (UCBT) in childhood acute myeloid leukemia (AML) have not been previously reported. We analyzed 95 children receiving UCB transplants for AML (20 in first complete remission [CR1], 47 in CR2, and 28 in more advanced stage). Poor prognosis cytogenetic abnormalities were identified in 29 cases. Most patients received a 1 or 2 HLA antigens-mismatched UCB transplants. The median number of collected nucleated cells (NCs) was 5.2 x 107/kg. Cumulative incidence (CI) of neutrophil recovery was 78% +/- 4%, acute graft-versus-host disease (GVHD) was 35% +/- 5%, and 100-day transplantation-related mortality (TRM) was 20% +/- 4%. In multivariable analysis, a collected NC dose higher than 5.2 x 107/kg was associated with a lower 100-day TRM. The 2-year CI of relapse was 29% +/- 5% and was associated with disease status. The 2-year leukemia-free survival (LFS) was 42% +/- 5% (59% +/- 11% in CR1, 50% +/- 8% in CR2, and 21% +/- 9% for children not in CR). Children with poor prognosis cytogenetic features had similar LFS compared with other patients (44% +/- 11% vs 40% +/- 8%). In CR2, LFS was not influenced by the length of CR1 (53% +/- 11% in CR1 < 9.5 months compared with 50% +/- 12% in later relapses). We conclude that UCBT is a therapeutic option for children with very poor-prognosis AML and who lack an HLA-identical sibling.

Acute Disease↗

PubMed2002

The architecture of interphase chromosomes and gene positioning are altered by changes in DNA methylation and histone acetylation.

Wheat nuclei have a remarkably well defined interphase organisation, and we have made use of this to determine the relationship between interphase chromosome organisation, the positioning of specific transgenes and induced changes in DNA methylation and histone acetylation, using in situ hybridisation and confocal 3D imaging. After germinating seeds either in the presence of 5-Azacytidine (5-AC), which leads to DNA hypomethylation, or trichostatin A (TSA), which results in histone hyperacetylation, the architecture of the interphase chromosome arms changes significantly even though the overall Rabl configuration is maintained. This suggests that specific chromosome segments are remodelled by these treatments but that there is a strong link of both centromeres and telomeres to the nuclear envelope. In lines carrying multiple transgene integrations at widely separated sites, we show that the multiple transgenes, which are usually colocalised during interphase, are dispersed after 5-AC or TSA treatment and that there is an increase in transgene activity. This suggests that the colocalisation/dispersion of the transgenes may be a function of specific interphase chromosome organisation and that these lines containing multiple transgene copies may all be partially transcriptionally repressed.

Acetylation↗

PubMed2002

Results of consecutive trials for children newly diagnosed with acute myeloid leukemia from the Australian and New Zealand Children's Cancer Study Group.

Despite improvements in the treatment of acute myeloid leukemia (AML), approximately 50% of children die of the disease. Clinical trials in adult patients with AML indicate that idarubicin may have superior efficacy when compared to daunorubicin in the remission-induction phases of chemotherapy. We conducted consecutive clinical trials in children with newly diagnosed AML in which daunorubicin (group 1, n = 102) or idarubicin (group 2, n = 160) was used during the remission-induction (RI) and the early consolidation phases of chemotherapy. Idarubicin was given at a dose of either 10 mg/m(2) (group 2A, n = 106) or 12 mg/m(2) (group 2B, n = 53). A high rate of RI was achieved for all groups (95% group 1, 90% group 2A, 94% group 2B). There were no significant differences in 5-year event-free survival (EFS) or in overall survival (OS) when the 3 groups were compared (group 1: EFS 50%, OS 56%; group 2A: EFS 50%, OS 60%; group 2B: EFS 34%, OS 50%). RI deaths resulting from treatment toxicity were low-2% for group 1 and 5% for group 2. More gastrointestinal, pulmonary, and renal toxicity but fewer infections were observed in patients receiving idarubicin (P <.001, P =.04, P =.03, respectively). Following RI chemotherapy, all patients received 3 to 4 more courses of identical chemotherapy and then underwent either autologous (n = 156) or an allogeneic bone marrow transplantation (BMT) (n = 35). OS was higher in allogeneic BMT patients than in autologous BMT patients (79% vs 63%; P =.23). We conclude that daunorubicin is as effective as idarubicin for remission-induction therapy for childhood AML and has reduced toxicity.

Adolescent↗

PubMed2002

Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission.

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.

Adolescent↗

PubMed2002

Allogeneic bone marrow transplantation: cure for familial Mediterranean fever.

We describe data on a 7-year-old girl with congenital dyserythropoietic anemia (CDA), who also had familial Mediterranean fever (FMF). Repeated transfusions required since the age of 6 months to treat her CDA led to iron overload and a persistently high ferritin level. Her relapsing FMF made effective iron chelation therapy very difficult. Consequently, at the age of 4 years, she underwent allogeneic, sibling bone marrow transplantation (BMT). During conditioning for her BMT, symptoms of FMF, including splenomegaly, arthritis, and recurrent abdominal pain, began to resolve and she was gradually weaned off colchicine. Now, 2 years after the transplantation, she remains free from FMF symptomatology and is off all immunosuppressants. This case demonstrates that symptoms of FMF can be alleviated by the therapy used during allogeneic BMT. In this patient it is likely that the missing factor in FMF is now being provided by granulocytes derived from the stem cells within transplanted bone marrow.

Anemia, Dyserythropoietic, Congenital↗