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Biomedical subjects

P Price

Publications and source records attributed to P Price.

At least 19 recordsLinked to original sources
PubMed2003

Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane.

Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.

Antineoplastic Agents↗
PubMed2003

Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.

PURPOSE: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. PATIENTS AND METHODS: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics. RESULTS: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m2/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.242 +/- 0.4), compared with [11C]XR5000 given alone (0.209 +/- 0.04; P <.05), indicating that tumor drug exposure was not saturated [corrected]. CONCLUSION: The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.

Acridines↗
PubMed2003

A Gambian TNF haplotype matches the European HLA-A1,B8,DR3 and Chinese HLA-A33,B58,DR3 haplotypes.

Caucasians carry TNFA-308*2 in the 8.1 ancestral haplotype (AH) (HLA-A1,B8,DR3). In Gambians, TNFA-308*2 occurs without HLA-B8 or -DR3, suggesting an independent effect of TNFA-308 on disease. Hence we sought a segment of the 8.1 AH in Gambians. BAT1 (intron 10)*2 was selected as a specific marker of the haplotype and was found with TNFA-308*2 in Gambians. Samples homozygous at TNFA-308 and BAT1 (intron 10) demonstrated identity between the African TNFA-308*2 haplotype, the 8.1AH and the Asian diabetogenic 58.1AH (HLA-A33,B58,DR3) across a region spanning BAT1, ATP6G, IKBL, LTA, TNFA, LTB, LST-1 and AIF-1. Conservation of this block in geographically distinct populations suggests a common evolutionary origin and challenges current views of the role of TNFA-308*2 in disease.

Asian People↗
PubMed2003

Polymorphisms in lymphotoxin alpha and CD14 genes influence TNFalpha production induced by Gram-positive and Gram-negative bacteria.

Improved understanding of how host genetic variation affects resistance to microbial pathogens could lead to better treatment and/or prevention of infectious diseases. The lymphotoxin alpha (LTA)+250 and CD14-159 polymorphisms are associated with differences in susceptibility or outcome to several infections. We stimulated peripheral blood mononuclear cells (PBMC) from 22 healthy individuals with purified lipopolysaccharide (LPS), heat-killed Escherichia coli or Streptococcus pneumoniae. TNF alpha intracellular protein levels were measured by flow cytometry and mRNA was quantitated by RT-PCR. TNF alpha mRNA levels were higher in LTA+250GG subjects after 4 h incubation with LPS compared with LTA+250AA (T test, P=0.001). In contrast, after 8 h incubation with S. pneumoniae, there was slightly more TNF alpha mRNA in cells from LTA+250AA subjects. After 4 h incubation with LPS or E. coli, CD14-159TT subjects had higher TNF alpha mRNA levels than CD14-159CC (P=0.05, 0.033, respectively). Neither polymorphism affected the proportion of cells expressing intracellular TNF alpha protein. This suggests that the polymorphisms affected transcription and that other regulatory mechanisms affect production of TNF alpha protein. The effect of these two polymorphisms on TNF alpha mRNA production is stimulus dependent, with opposite effects observed for Gram-positive and Gram-negative stimuli.

Genetic Predisposition to Disease↗
PubMed2003

Distribution of human CD30 gene promoter microsatellite alleles in healthy and human immunodeficiency virus-1 infected populations.

The human CD30 gene, found on chromosome 1; 1p36, contains a microsatellite of the type [(CCAT)2-12CCACTTATGCAT]n within the promoter. As the microsatellite has been shown to be both polymorphic and involved in the transcriptional regulation of this gene, it is of potential interest with respect to interindividual differences in CD30 expression. Here we describe a method for determining length variation of this repeat region and determine the frequency and distribution of alleles of the CD30 microsatellite within the Western Australian population. As soluble CD30 levels are predictive for disease associated with human immunodeficiency virus (HIV)-1 infection, we also determined allele frequencies in an HIV+ cohort.

HIV Infections↗
PubMed2003

Raltitrexed plus radiotherapy for the treatment of unresectable/recurrent rectal cancer: a phase I study.

BACKGROUND: Current consensus is that a combination of radiotherapy and chemotherapy may provide the optimal treatment for patients with unresectable rectal cancer. Raltitrexed has proven efficacy in the treatment of advanced colorectal cancer and has an acceptable toxicity profile. The aim of this phase I study was to determine the recommended dose of raltitrexed in combination with radiotherapy in patients with unresectable/recurrent rectal cancer. PATIENTS AND METHODS: Patients were treated with radiotherapy (25 fractions at 2.0 Gy per fraction) five times per week for 5 weeks. Raltitrexed was administered on days 1 and 22 at 2.0, 2.6 and 3.0 mg/m(2). RESULTS: A total of 20 patients were entered into the study. Dose-limiting toxicities were recorded in three of 20 patients following the first dose of raltitrexed; one patient at 2.6 mg/m(2) (grade 3 diarrhoea, grade 3 neutropenia and grade 2 pyrexia) and two patients at 3.0 mg/m(2) (one grade 3 neutropenia and one grade 4 diarrhoea). The most common non-haematological and haematological treatment-related adverse events were diarrhoea (11 of 20, two grade 3, one grade 4) and leukopenia (eight of 20, one grade 3, one grade 4), respectively. CONCLUSIONS: The recommended dose of raltitrexed in combination with radiotherapy for future studies is 2.6 mg/m(2).

Adult↗
PubMed2003

The use of a new overlay mattress in patients with chronic pain: impact on sleep and self-reported pain.

OBJECTIVE: To evaluate the use of an air flotation mattress overlay in patients with chronic pain. DESIGN: Four-week prospective AB design. SETTING: The mattress overlay was used in a community setting. SUBJECTS: Adult patients attending an outpatients clinic in a department of rheumatology, with chronic pain plus sleep problems, or pain sufficient to disturb sleep. INTERVENTIONS: An inexpensive low-pressure inflatable mattress overlay (Repose), which is readily portable and has no electrical supply, was introduced to the patients. They were encouraged to use the support surface every night. MAIN OUTCOME MEASURES: The primary outcome was measured by self-reported changes in sleep quantity and frequency of sleep disturbance. Secondary outcomes were self-reported changes in pain and use of analgesia, verified by medical notes. RESULTS: Nineteen female patients (mean age 61 years) completed the study. At baseline, mean length of sleep time was 3.8 h, with mean of 4.9 interruptions of mean 25.3 min: week 4, mean sleep time = 6.4 h, with a mean of 2.3 interruptions for mean 14.2 min (all measures p < 0.001). At baseline, median pain during the day was 6 and at night-time was 7; by week 4 a reduction in pain was reported both for the day (median = 5) and the night (median = 5) (both p < 0.001). Thirteen patients reported a reduction in the use of analgesia during the study. CONCLUSIONS: In this pilot study of a new mattress overlay, statistically significant improvements in sleep and pain were noted over a four-week period.

Adult↗
PubMed2003

Expression of RANKL and OPG mRNA in periodontal disease: possible involvement in bone destruction.

Periodontitis is a complex, multifactorial process affected by bacterial plaque-components and host defense mechanisms. Inflammation of the periodontitium may lead the destruction of the underlying ligament and alveolar bone. Receptor activator of NF-kappaB ligand (RANKL), a novel TNF receptor-related protein is an important factor for osteoclast differentiation and activation. Given osteolysis by osteoclast has been demonstrated in periodontitis, we hypothesized that RANKL expression may be associated with bone destruction in periodontitis. We used semi-quantitative RT-PCR to compare the gene expression of RANKL and osteoprogerin (OPG), a decoy receptor of RANKL, between moderate and advanced periodontitis, and healthy subjects. The level of RANKL mRNA was highest in advanced periodontitis. In contrast, the level of OPG mRNA in both advanced and moderate periodontitis was lower than that in the healthy group. It appears that the ratio of RANKL to OPG mRNA in periodontitis has increased. To determine the localization of RANKL gene transcripts in gingival tissue at the cellular level, in situ hybridization was performed using digoxigenin-labeled specific riboprobes. RANKL mRNA was expressed in inflammatory cells, mainly lymphocyte and macrophages. In addition, proliferating epithelium in the vicinity of inflammatory cells expressed high levels of RANKL mRNA. In short, our data suggest that up regulation of RANKL mRNA in both inflammatory cells and epithelium may be associated with the activation of osteoclastic bone destruction in periodontitis.

Adult↗
PubMed2002

Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients.

A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m(-2) intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1-18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine.

Adult↗
PubMed2002

Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin.

There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone-->Raf1-->Mitogenic Extracellular Kinase-->Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-(14)C)choline and (methyl-(14)C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-(14)C)choline uptake, (methyl-(14)C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-(11)C)choline may be a useful pharmacodynamic marker for the non-invasive evaluation of geldanamycin analogues.

Benzoquinones↗
PubMed2002

Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients.

Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.

Animals↗
PubMed2002

The EORTC Laboratory Research Division. European Organisation for Research and Treatment of Cancer.

The Laboratory Research Division (LRD) of the EORTC currently consists of five Groups with expertise that includes pre-clinical drug development, all aspects of cancer pharmacology, clinically-relevant receptor and biomarker studies, functional imaging and contemporary pathology. The LRD provides a Europewide resource for cancer clinical trials with particular expertise in the evolving field of translational research. In the development of therapies designed to exploit the molecular and cellular pathology of cancer, it is essential that translational research is included at all stages and the EORTC, through the LRD, has access to such expertise. In addition to providing support for drug development and clinical trials, the LRD represents a unique forum for the development of contemporary translational research expertise, the establishment of quality standards and the education of young laboratory and clinical scientists embarking on careers in oncology.

Europe↗
PubMed2002

Common HLA-B8-DR3 haplotype in Northern India is different from that found in Europe.

The aim of this study was to determine whether a common diabetic haplotype, including human leukocyte antigen (HLA)-B8 and HLA-DR3, in Northern India is the same haplotype as the European HLA-B8-DR3 haplotype. DNA samples from Northern Indian subjects selected on the basis of HLA-B8 and HLA-DR3 were tested for microsatellite and single nucleotide polymorphism alleles throughout the major histocompatibility complex (MHC). It was found that the Indian samples represent a conserved haplotype in which all alleles were shared by Indian subjects with HLA-B8 and HLA-DR3, but were different to those that are characteristic of the European 8.1 ancestral haplotype. The Indian and European haplotypes share HLA-B*0801, HLA-DRB1*0301 and HLA-DQB1*02 but differ for subtypes of HLA-Cw*07 and HLA-DRB3 and all central MHC alleles tested. In contrast, Indian subjects selected on the basis of HLA-B58 ( 1-17) and HLA-DR3 shared the same alleles at other MHC loci as have been described in the common Chinese haplotype with HLA-B58/17 and HLA-DR3. A third haplotype, HLA-B50/21 and HLA-DR3, was also found to be highly conserved but shares little in common with the other two HLA-DR3-containing Indian haplotypes.

Diabetes Mellitus, Type 1↗
PubMed2002

Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART.

OBJECTIVES: We have previously described immune restoration diseases (IRD) associated with asymptomatic opportunistic infections presenting in immunodeficient HIV patients responding to highly active antiretroviral therapy (HAART). Here we address the question of whether patients with a history of IRD exhibit persistent immune activation, shown by elevated levels of interleukin-(IL)-6 and soluble IL-6 receptor (sIL-6R). METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma were collected from HIV patients with nadir CD4 T cell counts of < 80/microL and who had achieved immune reconstitution after HAART with (n=14) or without (n=15) experiencing IRD, severely immunodeficient (SID) patients with < 80 CD4 T cells/microL (n=8) and HIV seronegative controls (n=15). PBMC production and plasma levels of IL-6, sIL-6R and interferon (IFN)-gamma (PBMC only) were measured by enzyme linked immunosorbent assay (ELISA). Intracellular flow cytometry was used to determine the predominant cellular source of IL-6 in HIV patients and controls. RESULTS: Unstimulated PBMC from IRD patients produced significantly higher amounts of IL-6 and sIL-6R than non-IRD patients and HIV seronegative controls. The sIL-6R concentration was also significantly higher in supernatants from mitogen-stimulated PBMC from IRD patients compared to non-IRD patients. The production of IFN-gamma did not differ between IRD and non-IRD patients. IRD patients had significantly higher plasma levels of IL-6 compared to non-IRD patients, SID patients and controls. Monocytes were the predominant source of IL-6 in both HIV patients and controls. CONCLUSIONS: Patients with a history of IRD after HAART have elevated levels of IL-6 and sIL-6R.

Adult↗
PubMed2002

Interleukin-1 gene polymorphism disease activity and bone mineral metabolism in rheumatoid arthritis.

OBJECTIVE: To determine whether interleukin-1 alpha and 1 beta gene polymorphism is associated with rheumatoid arthritis disease activity and bone mineral metabolism, and whether there is any relationship between IL-1 beta and rheumatoid arthritis (RA) motif gene. METHODS: IL-1 gene polymorphisms were analyzed in 65 RA patients who met American College of Radiology (ACR) criteria and 60 controls. From genomic DNA, 2 polymorphisms in each gene for IL1 alpha-889 and IL-1 beta + 3953 were typed by PCR-RFLP and HLA-DRB1 allele typing was also undertaken by PCR-SSOP. Some clinical and laboratory parameters were collected. The allelic frequencies and carriage rates were compared between RA patients and controls and between patients with active and quiescent disease. Comparison was also made between IL-1 polymorphism and parameters of bone mineral metabolism and between patients with the HLA-DRB1 RA motif plus IL-1 beta 2 and patients without the two alleles. Fisher test and the analysis of variance was used to analyze the data. RESULTS: There was no significant difference in the frequency and carriage rate of IL-1 alpha polymorphisms between RA patients and the controls. The beta 2/2 genotype of IL-1 beta was more common in female RA patients compared with controls (P = 0.001). A lower carriage rate of IL-1 beta 2 occurred in male RA patients (P = 0.001). A higher carriage rate of IL-1 alpha 2 is associated with a higher ESR (P = 0.008), HAQ score (P = 0.03), and vit-D3 (P < 0.001), but conversely a lower SJC (p = 0.002), a lower RF (P = 0.002) and a lower BMD at the lumbar spine (P = 0.001). A higher frequency of IL-1 alpha 1 is associated with a lower CRP value (P = 0.009). An increased IL-1 beta 2 carriage is associated with active rheumatoid disease as indicated by a higher CRP (P < 0.001), ESR (P < 0.001) and pain score (P = 0.001) and a higher BMD at the lumbar spine (P = 0.007), lower vit-D3 and. Udpd/Crea level The presence of the HLA DRB1 RA motif and IL-1 beta allele 2 at same time did not contribute to disease activity. CONCLUSION: Polymorphisms of the IL-beta gene may affect the RA occurrence. Carriage of IL-1 beta 2 polymorphisms is associated with more active disease in RA and the presence of both the IL-1 alpha 2 and the IL-1 beta 1 allele in RA influences bone resorption.

Alleles↗