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Biomedical subjects

A Hamilton

Publications and source records attributed to A Hamilton.

At least 19 recordsLinked to original sources
PubMed2006

BCR-ABL activity and its response to drugs can be determined in CD34+ CML stem cells by CrkL phosphorylation status using flow cytometry.

In chronic myeloid leukaemia, CD34(+) stem/progenitor cells appear resistant to imatinib mesylate (IM) in vitro and in vivo. To investigate the underlying mechanism(s) of IM resistance, it is essential to quantify Bcr-Abl kinase status at the stem cell level. We developed a flow cytometry method to measure CrkL phosphorylation (P-CrkL) in samples with <10(4) cells. The method was first validated in wild-type (K562) and mutant (BAF3) BCR-ABL(+) as well as BCR-ABL(-) (HL60) cell lines. In response to increasing IM concentration, there was a linear reduction in P-CrkL, which was Bcr-Abl specific and correlated with known resistance. The results were comparable to those from Western blotting. The method also proved to be reproducible with small samples of normal and Ph(+) CD34(+) cells and was able to discriminate between Ph(-), sensitive and resistant Ph(+) cells. This assay should now enable investigators to unravel the mechanism(s) of IM resistance in stem cells.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Analysis of the incidence of infectious pancreatic necrosis mortality in pedigreed Atlantic salmon, Salmo salar L., populations.

A total of 77,124 Atlantic salmon post-smolts, representing 197 full-sib families produced by 149 males and 197 females, experienced a field challenge from infectious pancreatic necrosis virus (IPNV), following transfer to three separate seawater sites. The first IPN mortality was observed 45 days after transfer, and the duration of the epidemic varied between 37 and 92 days among sites. Mortalities were traced to their parental families by PIT (Passive Integrated Transpondes) tag records and DNA genotyping. Full-sib family mean incidence of mortality was calculated for each family on each site. Heritabilities were estimated based on the heterogeneity of chi-square using incidence within half-sib families and the variance in incidence among full-sib families, both on the observed and underlying liability scale. The observed correlation among families across sites was used to estimate genetic correlations. The overall mortality rate was 10.8%, with only small differences between sites, ranging from 10.3% to 11.9%. Heritabilities on the liability scale were found to be moderate to strong, and ranged between 0.24 and 0.81, with a pooled estimate of 0.43, greater than is typically associated with disease traits. Genetic correlations among sites were all substantial, between 0.71 and 0.78, and indicated that a substantial component of the genetic variation displayed within sites was common to all. The results show that field challenges can yield very good genetic information on family differences in resistance, especially when replicated over sites, which may then be developed for use in selection for breeding strains of Atlantic salmon with greater resistance to IPN.

Animals↗
PubMed2005

Spatially resolved measurement of rock core porosity.

Density weighted, centric scan, Conical SPRITE MRI techniques are applied in the current work for local porosity measurements in fluid saturated porous media. The methodology is tested on a series of sandstone core samples. These samples vary in both porosity and degree of local heterogeneity due to bedding plane structure. The MRI porosity measurement is in good agreement with traditional gravimetric measurements of porosity. Spatially resolved porosity measurements reveal significant porosity variation in some samples. This novel MRI technique should have applications to the characterization of local porosity in a wide variety of porous media.

Journal Article↗
PubMed2004

Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer.

The use of taxanes in early breast cancer is increasing. However, there are few mature studies of taxanes in this setting, and their role is uncertain. Our systematic review of randomised trials of adjuvant or neoadjuvant systemic therapy identified ten reported trials comparing a taxane-containing group with a non-taxane-containing control group in women with early breast cancer. Four of five neoadjuvant trials showed higher rates of complete response with taxanes, although differences were not significant. All five adjuvant trials showed improvements in disease-free survival with taxanes, and these improvements were significant in three trials and independent of oestrogen-receptor status. Two trials showed a significant improvement in overall survival. These results support the use of adjuvant taxanes in women with early breast cancer and involved lymph nodes. Longer follow-up of these trials and results from continuing trials are needed to clarify the best use of taxanes in early breast cancer.

Adult↗
PubMed2004

Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD.

The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44 +/- 13% pred): 96 patients received 18 microg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patient's maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105 +/- 40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9 +/- 0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.

Aged↗
PubMed2003

Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study.

PURPOSE: To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer. PATIENTS AND METHODS: Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen. RESULTS: A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94). CONCLUSION: Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.

Adolescent↗
PubMed2003

Doxorubicin-paclitaxel: a safe regimen in terms of cardiac toxicity in metastatic breast carcinoma patients. Results from a European Organization for Research and Treatment of Cancer multicenter trial.

BACKGROUND: The potential cardiotoxicity of the doxorubicin-paclitaxel regimen, when paclitaxel is given shortly after the end of the anthracycline infusion, is an issue of concern, as suggested by small single institution Phase II studies. METHODS: In a large multicenter Phase III trial, 275 anthracycline naive metastatic breast carcinoma patients were randomized to receive either doxorubicin (60 mg/m(2)) followed 30 minutes later by paclitaxel (175 mg/m(2) 3-hour infusion; AT) or a standard doxorubicin-cyclophosphamide regimen (AC; 60/600 mg/m(2)). Both treatments were given once every 3 weeks for a maximum of six cycles. Close cardiac monitoring was implemented in the study design. RESULTS: Congestive heart failure (CHF) occurred in three patients in the AT arm and in one patient in the AC arm (P = 0.62). Decreases in left ventricular ejection fraction to below the limit of normal were documented in 33% AT and 19% AC patients and were not predictive of CHF development. CONCLUSIONS: AT is devoid of excessive cardiac risk among metastatic breast carcinoma patients, when the maximum planned cumulative dose of doxorubicin does not exceed 360 mg/m(2).

Adenocarcinoma↗
PubMed2003

A method for in-vivo analysis for regional arterial wall material property alterations with atherosclerosis: preliminary results.

Atherosclerosis is a diffuse arterial disease developing over many years and resulting in a complicated three-dimensional arterial morphology. The arterial wall material properties have been demonstrated to show regional alterations with atheroma development and growth. We present a mechanical analysis of diseased arterial segments reconstructed from intravascular ultrasound images in order to quantitatively identify regional alterations in the elastic constants with atherosclerotic lesions. We employ a finite element and a displacement sensitivity analysis to divide the arterial segment into regions with different material properties and use an optimization algorithm to identify the elastic constants in these regions. The results with regional variations identified with this method correlated qualitatively with the extent and location of atherosclerotic lesions identified by visual inspection of the affected arteries. The optimized elastic modulus in regions affected by early atherosclerotic lesions ranged from 90.9 to 93.0 kPa where as the corresponding magnitudes in normal arterial segments ranged from 97.9 to 101.0 kPa. This method can be potentially employed to identify the extent and location of atherosclerotic lesions in a systematic analysis and may potentially be used for the early detection of lesion growth.

Animals↗
PubMed2003

Locally advanced/inflammatory breast cancers treated with intensive epirubicin-based neoadjuvant chemotherapy: are there molecular markers in the primary tumour that predict for 5-year clinical outcome?

BACKGROUND: Locally advanced and/or inflammatory breast cancer (LABC) is a heterogeneous disease. Molecular markers may help to understand this heterogeneity. This paper reports the results of a study assessing the potential prognostic or predictive value of HER-2, p53, cyclinD1, MIB1, ER and PgR expression by immunohistochemistry from patients included in an EORTC-NCIC-SAKK trial. PATIENTS AND METHODS: A total of 448 patients with a cytological or histological diagnosis of LABC were randomised into a trial comparing two anthracycline-based neoadjuvant regimens. Chemotherapy was followed by standard locoregional therapy. Survival was comparable in both arms. We collected and analysed centrally paraffin-embedded tumour specimens from 187 (72.5%) of 258 patients that had a histological diagnosis. RESULTS: Of the patients included in this molecular marker study 114 relapsed and 91 died. In the multivariate analysis p53 positivity was associated with a shorter progression-free survival [hazard ratio (HR) = 1.96; 95% CI 1.33-2.91; P = 0.0008) and a shorter overall survival (HR = 1.98; 95% CI 1.28-3.06; P = 0.002). PgR positivity predicted for a longer overall survival (HR = 0.54; 95% CI 0.35-0.83; P = 0.0045). CONCLUSIONS: p53 was an independent factor predicting for survival. In order to clarify whether p53 is a pure prognostic and/or a predictive factor, a phase III trial is being conducted (EORTC 10994/BIG 00-01 study) using functional assay in yeast from frozen tumour samples.

Administration, Oral↗
PubMed2003

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer.

BACKGROUND: Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. PATIENTS AND METHODS: Patients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. RESULTS: Blinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. CONCLUSIONS: Exemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.

Adult↗
PubMed2002

An EORTC-IDBBC phase I study of gemcitabine and continuous infusion 5-fluorouracil in patients with metastatic breast cancer resistant to anthracyclines or pre-treated with both anthracyclines and taxanes.

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

Adult↗
PubMed2002

EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. European Organization for Research and Treatment of Cancer.

BACKGROUND: We performed a phase I study of polyethylene glycol (pegylated, Stealth) liposomal doxorubicin (Caelyx, Doxil) using a prolonged (6-week) dose interval to reduce the incidence of skin toxicity that was dose-limiting at more conventional dose intervals, and which appeared to be schedule dependent. PATIENTS AND METHODS: Eligible for the study were metastatic breast cancer patients who had received a maximum of one prior therapy for metastatic disease. The defined dose levels were 60, 70, 80 and 90 mg/m2. RESULTS: Twenty patients were assessed at starting doses of 60 mg/m2 (n = 9) or 70 mg/m2 (n = 11). The dose-limiting toxicity was mucositis. Severe skin toxicity was not observed at the 60 mg/m2 dose level, and occurred in only one patient treated at 70 mg/m2. Significant neutropenia, alopecia, and nausea and vomiting were rare events. No clinical cardiac events occurred, despite a median cumulative doxorubicin dose of 323 mg/m2 (range 5-630 mg/m2). Partial responses were documented in five patients. Pharmacokinetics were assessed in 15 patients, and confirmed the long terminal half-life of the agent (median 77 h) demonstrated in earlier studies. CONCLUSIONS: The recommended dose of Caelyx/Doxil using this schedule is 60 mg/m2 every 6 weeks. This is a safe and effective regimen that permits prolonged administration of anthracycline to patients with metastatic breast cancer.

Adult↗
PubMed2001

Beware: toxic mold.

Explore the source record for details and available documents.

Air Pollution, Indoor↗
PubMed2001

Replicating potato spindle tuber viroid RNA is accompanied by short RNA fragments that are characteristic of post-transcriptional gene silencing.

The low molecular weight fraction of tomato plants inoculated with potato spindle tuber viroid (PSTVd) contains a population of short PSTVd-specific RNAs of either polarity. The main constituents were RNAs of 22 and 23 nt representing different domains of the viroid genome. The occurrence of such distinct RNA species indicated that the nuclear replicating PSTVd RNA induces post-transcriptional gene silencing. The short RNAs were slightly more abundant at 30 days post-inoculation than at later stages and were present in plants infected with a mild, severe or lethal isolate of PSTVD: There was no apparent correlation between the quantity of small PSTVd-specific RNAs and the degree of virulence of the viroid isolate.

Blotting, Northern↗
PubMed2001

Recall bias in self-reported melanoma risk factors.

The evidence implicating sun exposure in the etiology of melanoma derives largely from case-control studies in which the retrospective assessment of sun exposure suggests potential for significant recall bias. Previous attempts at characterizing and quantifying that bias have had significant methodological limitations. In the International Twin Study, a case-control study of melanoma risk factors in twins conducted from 1980 to 1991, the authors asked melanoma cases and their co-twins to quantify their own exposures and asked which twin had the greater exposure. Recall bias was investigated by assuming that, if bias had occurred, the odds ratio based on the case's response would differ significantly from the odds ratio based on the co-twin's response. Case-derived odds ratios were higher than the odds ratios for the controls for sunbathing in childhood and adulthood and for mole frequency and freckling in childhood, suggesting some recall bias. The odds ratios for ease of burning and tanning appeared unbiased. The belief that sunlight was a cause of melanoma appeared related to an increased odds ratio for sunbathing as a child. There is a continuing need to carefully assess recall bias in the study of melanoma risk factors.

Adolescent↗
PubMed2001

Phylogeny of Limia (Teleostei: Poeciliidae) based on NADH dehydrogenase subunit 2 sequences.

Complete sequences for the mitochondrial gene NADH Dehydrogenase 2 (ND2) and partial sequences for the tRNA-Met and tRNA-Trp genes were obtained for 11 populations of the poeciliid fish genus (or subgenus) Limia, including species from Hispaniola, Cuba, Jamaica, and Grand Cayman Islands. Additional sequences for Limia (2 species), Pamphorichthys (3), Poecilia (16), and Xiphophorus (1), all from the tribe Poeciliini, were extracted from GenBank, as was a sequence for Heterandria formosa, from the tribe Heterandriini. Phylogenetic analyses included parsimony, distance methods, and maximum-likelihood. Several Limia species groups that had been proposed based on morphological data were evaluated. The versicolor species group was strongly supported, as was the close relationship between the Cuban Limia vittata and the Grand Cayman Limia caymanensis. However, the proposed vittata species group was not upheld by the ND2 data. The phylogenetic position of Limia melanogaster, from Jamaica, was either sister to the versicolor species group or basal to all other included Limia species. Limia was found to be monophyletic; however, Limia species from the island of Hispaniola were not monophyletic. There was little support for any proposed sister group to Limia. The phylogeny was used to reconsider a previous comparative study of poeciliid courtship behavior and sexual dimorphism. The data indicated that there may have been two independent appearances of courtship display behavior in Limia; considering the tribe Poeciliini as a whole, there is evidence for as many as five appearances of display (including two within Limia), or a complex pattern of gains and losses of such behavior. The application of phylogenetic information to the comparative study did not refute the previously hypothesized correlation between the presence of a courtship display and the presence of sexual dimorphism in poeciliid fish.

Animals↗