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Biomedical subjects

A Hamilton

Publications and source records attributed to A Hamilton.

At least 37 records · Page 2Linked to original sources
PubMed2001

Phase III data on Caelyx in ovarian cancer.

Impressive responses to pegylated liposomal doxorubicin (Doxil/Caelyx) in pretreated ovarian cancer patients during phase I studies led to a phase II study in platinum and taxane failures. A 26% objective response rate was obtained in this trial and this was confirmed by further phase II studies. The stage was set for a phase III trial in comparison with topotecan, the drug that had become standard in the salvage treatment of patients who were platinum-refractory or -resistant. The completed trial indicates equivalence of results in terms of response rates, time to treatment failure and survival. Differences exist in the toxicity spectrum and in subset analysis according to platinum resistance. On this basis, Caelyx is being positioned as part of chemotherapeutic regimens in first-line phase III trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Pulsatile flow simulation in arterial vascular segments with intravascular ultrasound images.

Previous studies have indicated a correlation between local variation in wall shear stress in arterial blood flow and atheroma development. The purpose of this study was to analyze the hemodynamics in vascular segments from morphologically realistic three-dimensional (3D) reconstruction, and to compare the computed wall shear stress in a compliant vascular segment model and the corresponding rigid walled model. Cross-sectional images of the segments of femoral and carotid arteries in five Yucatan miniswine were obtained using intravascular ultrasound (IVUS) imaging and the segment geometry was reconstructed at different times in the cardiac cycle. The actual measured wall motion from the reconstruction was employed to specify the moving boundaries for simulation of physiological distensibility. Velocity profiles and wall shear stress were computed using unsteady computational fluid dynamics analysis. The computed results revealed that the maximum wall shear stress in the compliant model was approximately 4-17 percent less than that in the rigid model if the wall motion is larger than 10 percent. Our analysis demonstrates that inaccuracies due to inflow velocity profile can be minimized by the extension of the model upstream. The phase angle between the diameter change and wall shear is affected by the local changes in geometry of the arteries. These simulations can be potentially used to analyze the effect of regional wall motion changes in the presence of atherosclerotic lesions on the local fluid dynamics and to correlate the same with subsequent growth of the lesions.

Animals↗
PubMed2001

An EORTC phase I study of epirubicin in combination with fixed doses of cyclophosphamide and infusional 5-fu (CEF-infu) as primary treatment of large operable or locally advanced/inflammatory breast cancer.

PURPOSE: The association of continuous infusion 5-fluorouracil, epirubicin (50 mg/m2 q 3 weeks) and a platinum compound (cisplatin or carboplatin) was found to be very active in patients with either locally advanced/inflammatory (LA/I) [1, 2] or large operable (LO) breast cancer (BC) [3]. The same rate of activity in terms of response rate (RR) and response duration was observed in LA/I BC patients when cisplatin was replaced by cyclophosphamide [4]. The dose of epirubicin was either 50 mg/m2 [ 1, 2, 3] or 60 mg/m2/cycle [4]. The main objective of this study was to determine the maximum tolerated dose (MTD) of epirubicin when given in combination with fixed doses of cyclophosphamide and infusional 5-fluorouracil (CEF-infu) as neoadjuvant therapy in patients with LO or LA/I BC for a maximum of 6 cycles. PATIENTS AND METHODS: Eligible patients had LO or LA/I BC, a performance status 0-1, adequate organ function and were <65 years old. Cyclophosphamide was administered at the dose of 400 mg/m2 day 1 and 8, q 4 weeks and infusional 5-fluorouracil 200 mg/m2/day was given day 1-28, q 4 weeks. Epirubicin was escalated from 30 to 45 and to 60 mg/m2 day 1 and 8; dose escalation was permitted if 0/3 or 1/6 patients experienced dose limiting toxicity (DLT) during the first 2 cycles of therapy. DLT for epirubicin was defined as febrile neutropenia, grade 4 neutropenia lasting for >7 days, grade 4 thrombocytopenia, or any non-haematological toxicity of CTC grade > or =3, excluding alopecia and plantar-palmar erythrodysesthesia (this toxicity was attributable to infusional 5-fluorouracil and was not considered a DLT of epirubicin). RESULTS: A total of 21 patients, median age 44 years (range 29-63) have been treated. 107 courses have been delivered, with a median number of 5 cycles per patient (range 4-6). DLTs on cycles I and 2 on level 1, 2, 3: grade 3 (G3) mucositis occurred in 1/10 patients treated at the third dose level. An interim analysis showed that G3 PPE occurred in 5/16 pts treated with the 28-day infusional 5-FU schedule at the 3 dose levels. The protocol was subsequently amended to limit the duration of infusional 5-fluorouracil infusion from 4 to 3 weeks. No G3 PPE was detected in 5 patients treated with this new schedule. CONCLUSIONS: This study establishes that epirubicin 60mg/m2 day 1 and 8, cyclophosphamide 400mg/m2 day 1 and 8 and infusional 5-fluorouracil 200 mg/m2/day day 1-21. q 4 weeks is the recommended dose level. Given the encouraging activity of this regimen (15/21 clinical responses) we have replaced infusional 5-fluorouracil by oral capecitabine in a recently activated study.

Adult↗
PubMed2001

Signal transduction pathways of IL-1beta-mediated iNOS in pulmonary vascular smooth muscle cells.

Interleukin (IL)-1beta is an important early mediator of inflammation in pulmonary artery smooth muscle cells. We previously reported that a geranylgeranyltransferase inhibitor elevated basal levels of inducible nitric oxide synthase (iNOS) and enhanced IL-1beta-mediated induction, suggesting that Rac or Rho small G proteins are candidates for antagonism of such induction. In this study, overexpression of constitutively active Rac1 or its dominant negative mutant did not affect IL-1beta induction of iNOS. Alternatively, treatment with Clostridium botulinum C3 exoenzyme, which ADP-ribosylates Rho, was associated with superinduction of iNOS, suggesting an inhibitory role for Rho. IL-1beta activated the three mitogen-activated protein kinase (extracellular signal-regulated kinases 1 and 2, c-Jun NH2-terminal kinase/stress-activated protein kinase, and p38) and the Janus kinase (JAK)-signal transducer and activator of transcription pathways. The former two pathways were not associated with IL-1beta-mediated iNOS induction, whereas the latter two appeared to have inhibitory roles in iNOS expression. These data suggest that a broad intracellular signaling response to IL-1beta in rat pulmonary artery smooth muscle cells results in elevated levels of iNOS that is opposed by the geranylgeranylated small G protein Rho as well as the p38 and JAK2 pathways.

Animals↗
PubMed2001

Estramustine potentiates taxane in prostate and refractory breast cancers.

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Breast Neoplasms↗
PubMed2001

Nonsteroidal and steroidal aromatase inhibitors in breast cancer.

Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.

Anastrozole↗
PubMed2001

Interleukin 8 is an autocrine growth factor and a surrogate marker for Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common tumor associated with HIV-1 infection. Here, we report the expression, regulation, and biological effect of interleukin (IL)-8 in KS. AIDS-KS cell lines expressed higher levels of IL-8 than either human umbilical vein endothelial cells (HUVECs), human aortic smooth muscle (AoSM) cells or fibroblast cells (T1). The inflammatory cytokine IL-1beta up-regulated IL-8 expression in a time- and concentration-dependent manner in KS cell lines. IL-8 antisense oligonucleotides specifically reduced IL-8 mRNA and protein levels and inhibited KS cell growth in a dose-dependent manner. In addition, supernatant from a KS cell line induced the growth of HUVECs and angiogenesis in chicken chorioallantoic membrane assays, both of which were inhibited by IL-8 neutralizing antibody. Serum levels of IL-8 were also elevated in KS cases compared with matched controls. Modulation of IL-8 may thus be of therapeutic value in this disease.

Animals↗
PubMed2000

Developing consensus: mercury science and policy in the NAFTA countries (Canada, the United States and Mexico).

The international science community has recognized methylmercury in the aquatic food chain, as a potential environmental and human health risk. As a result, countries around the world have implemented a number of mercury management initiatives. The United States, Mexico and Canada in consultation with stakeholders are developing a trilateral North American Regional Action Plan (NARAP) on mercury. Through public involvement in the decision making process, the NARAP has offered opportunities for more transparency in transactions between governments, industry and stakeholders. In spite of the available scientific information, there are still important uncertainties associated with the mercury issue. These knowledge gaps include: the most appropriate methylmercury reference dose for sensitive groups; the percentage of the North American population that is at risk from methylmercury exposure; spatial and temporal mercury deposition patterns in each country; the link between mercury emissions, atmospheric deposition and methylmercury concentrations in fish; and the relative magnitude of contributions from natural and anthropogenic sources.

Animals↗
PubMed2000

Surface electrode somatosensory-evoked potentials in spinal surgery: implications for indications and practice.

STUDY DESIGN: A retrospective study of 442 major spinal operations with spinal cord monitoring performed in a University Hospital between 1982 and 1992 was performed. OBJECTIVES: To assess the reliability of the authors' method for monitoring by somatosensory-evoked potential recording, to determine criteria for intraoperative corrective action, and to redefine the need for the wake-up test. SUMMARY OF BACKGROUND DATA: The routine use of somatosensory-evoked potential monitoring in spinal surgery remains controversial. In Nottingham, the authors have used a method of recording from either scalp or high cervical electrodes. METHODS: The recordings and outcomes of all monitored spinal operations between the years 1982 and 1992 were reviewed. RESULTS: In 442 procedures, 23 technical failures (no reliable monitoring) occurred. Most technical failures were in patients with severe preoperative neurology, identifiable by somatosensory-evoked potential recording before operation. In the remaining 419 procedures, a significant intraoperative change in response occurred in 70 procedures (16.7%). Using the definitions of the American EEG Society, the authors identified 10 true-positives and 60 false-positives. There were no false-negatives. A wake-up test was performed if an amplitude drop greater than 50% from baseline value persisted after attempts to correct any possible identifiable intraoperative cause. This occurred in only 21 patients (5%). In the true-positive group, somatosensory-evoked potential recordings remained persistently abnormal despite an apparently normal subsequent wake-up test. The sensitivity of the method according to current definitions was 100% and the specificity 85.33%. CONCLUSIONS: Modified guidelines are needed for routine intraoperative use of somatosensory-evoked potential monitoring in spinal surgery. Such guidelines should avoid the term "false-positive" as currently defined and concentrate on the causative analysis of abnormal responses that warn of critical spinal cord dysfunction before that becomes irreversible and allow for appropriate action. Information from this monitoring method alerted the surgeon to the possible need for corrective action in an additional 9.78% of the reported patients, who traditionally would have been regarded as false-positives. A wake-up test still is indicated in patients with persistent suppression of their somatosensory-evoked potential despite correction of any identifiable cause and in cases of technical failure. The current method proved flexible, versatile, and reliable for future use.

Adolescent↗
PubMed2000

An RNA-dependent RNA polymerase gene in Arabidopsis is required for posttranscriptional gene silencing mediated by a transgene but not by a virus.

Posttranscriptional gene silencing is a defense mechanism in plants that is similar to quelling in fungi and RNA interference in animals. Here, we describe four genetic loci that are required for posttranscriptional gene silencing in Arabidopsis. One of these, SDE1, is a plant homolog of QDE-1 in Neurospora crassa that encodes an RNA-dependent RNA polymerase. The sde1 mutation was specific for posttranscriptional gene silencing induced by transgenes rather than by viruses. We propose that the role of SDE1 is to synthesize a double-stranded RNA initiator of posttranscriptional gene silencing. According to this idea, when a virus induces posttranscriptional gene silencing, the virus-encoded RNA polymerase would produce the double-stranded RNA and SDE1 would be redundant.

Amino Acid Sequence↗
PubMed2000

Characterization of acid phosphatase activities in the equine pathogen Streptococcus equi.

Acid phosphatases hydrolyse phosphomonoesters at acidic pH in a variety of physiological contexts. The recently defined class C family of acid phosphatases includes the 32 kDa LppC lipoprotein of Streptococcus equisimilis. To define further the distribution of acid phosphatases in the genus Streptococcus we have examined the equine pathogens Streptococcus equi subsp. equi and Streptococcus equi subsp. zooepidemicus. Whole cell assays indicated that these organisms possess two acid phosphatases with activity optima at pH 5.0 and pH 6.0-6.5 and that only the former of these was, like LppC, resistant to EDTA. Western blotting with a polyclonal anti-LppC antiserum revealed the presence of a cross-reactive 32 kDa protein in both organisms. The cross-reactive protein in S. equi was shown to be a surface accessible lipoprotein as its processing was inhibited by the antibiotic globomycin and it was released from whole cells by treatment with trypsin. The presence of DNA sequences homologous to the S. equisimilis lppC gene were confirmed by PCR. These data strongly suggest that Streptococcus equi subsp. equi and Streptococcus equi subsp. zooepidemicus produce a lipoprotein acid phosphatase homologous to LppC of S. equisimilis.

Acid Phosphatase↗
PubMed2000

HER2. a 'predictive factor' ready to use in the daily management of breast cancer patients?

The past few years have witnessed an exponential increase in studies trying to identify molecular markers in patients with breast tumours that might predict for the success or failure of hormonal therapy or chemotherapy. HER2, a tyrosine kinase membrane receptor of the epidermal growth factor receptor family, has been the most widely studied marker in this respect. This paper attempts to critically review to what extent HER2 may improve 'treatment individualisation' for the breast cancer patient.

Anthracyclines↗
PubMed2000

Infant vocabulary development assessed with a British communicative development inventory.

Communicative Development Inventories (CDIs) were collected from 669 British children aged between 1;0 and 2;1. Comprehension and production scores in each age group are calculated. This provides norming data for the British infant population. The influence of socioeconomic group on vocabulary scores is considered and shown not to have a significant effect. The data from British infants is compared to data from American infants (Fenson, Dale, Reznick, Bates, Thal & Pethick, 1994). It is found that British infants have lower scores on both comprehension and production than American infants of the same age.

Child Language↗
PubMed2000

EORTC 10941: A phase II study of liarozole in postmenopausal patients with 'chemotherapy-resistant' or 'potentially hormone sensitive' metastatic breast cancer.

Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: 'Chemotherapy Resistant' (unrestricted ER status, 1 or 2 prior chemotherapy regimens, 0-2 prior hormonal therapies) and 'Potentially Hormone Sensitive' (ER positive or unknown, 1 or 2 prior hormonal therapies with a substantial disease free interval or progression free survival, and no history of chemotherapy for metastatic disease). Liarozole was administered at 150-300 mg orally bid. The objective response rate was 12% in the 'Chemotherapy Resistant' group (n = 34), and 22% in the 'Potentially Hormone Sensitive' group (n = 37), with median response durations of 9 and 14 months, respectively. Median time to treatment failure was only 2 months in both groups, due largely to the significant percentage (24%) of patients who ceased treatment following excessive mucocutaneous and gastrointestinal toxicity. This adverse event profile will limit its use in breast cancer. Results of the 'ER negative' and 'Tamoxifen Refractory' groups will be reported in a future paper.

Adult↗
PubMed2000

The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2.

BACKGROUND: The selection of therapies for breast cancer is today based on prognostic features (chemotherapy, radiotherapy), hormone receptor status (hormonal therapy) and HER-2 status (trastuzumab therapy). HER-2, p53 and BCL-2 are tumour-related proteins that have the potential to further improve individualisation of patient management, by predicting response to chemotherapy, hormonal therapy and radiotherapy. MATERIALS AND METHODS: This paper reviews the rationale for the use of these proteins as predictive factors, as well as the published literature addressing the use of each one to predict response to hormonal therapy, chemotherapy and radiotherapy. RESULTS: HER-2, p53 and BCL-2 remain inadequately assessed as predictive factors in breast cancer. HER-2 evaluation is required for the selection of patients for trastuzumab (Herceptin) therapy, as trials of this therapy have been limited to HER-2 overexpressors. HER-2 overexpression may be predictive of resistance to hormonal therapy. Anthracyclines are effective therapy for breast cancer regardless of HER-2 status, but patients whose tumours overexpress HER-2 appear to receive the greatest relative benefit from this therapy. Studies of HER-2 as a predictor of response to CMF and to radiotherapy are inconclusive at this time. No data yet exist to support the use of p53 or BCL-2 as predictive factors in the therapy of breast cancer. CONCLUSIONS: At this point in time, there is inadequate evidence to support the use of HER-2, p53 or BCL-2 to guide the selection of hormonal therapy, chemotherapy or radiotherapy for breast cancer.

Anthracyclines↗
PubMed2000

Breast cancer stage at diagnosis and survival among patients with prior breast implants.

Longstanding concern exists regarding the potential for women with breast implants to experience delayed detection of breast cancer. Furthermore, survival among cosmetic breast implant patients who subsequently develop breast cancer is a concern. Since 1976, this institution has monitored cancer incidence in a cohort of 3182 women who underwent cosmetic breast augmentation between 1959 and 1981. The distributions of stage at diagnosis and survival of the 37 women who subsequently developed in situ or invasive breast cancer were compared with the observed population distributions. The distribution of stage at diagnosis for cosmetic breast implant patients who subsequently developed breast cancer was virtually identical to that of all breast cancer patients in Los Angeles County who were of the same age and race, and were diagnosed during the same time period. Furthermore, the 5-year survival rate of the 37 patients did not differ from that which would be expected based on rates established by the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. These results suggest that cosmetic breast implant patients are not at increased risk of delayed detection of breast cancer, nor do they suffer a poorer prognosis when breast cancer does occur. Although the number of breast cancer patients in this study is small, the results are highly consistent with the existing epidemiologic evidence related to breast cancer detection and survival among breast implant patients. Although breast implant patients should continue appropriate breast cancer screening behavior, there seems to be no cause for alarm.

Adult↗
PubMed2000

Potato virus X amplicons in arabidopsis mediate genetic and epigenetic gene silencing.

Amplicon transgenes from potato virus X (PVX) are based on a modified version of the viral genome and are efficient activators of post-transcriptional gene silencing (PTGS). To determine whether PVX amplicons activate PTGS in Arabidopsis, we used constructs based on the genome of PVX carrying a green fluorescent protein (GFP) reporter gene. Our analysis of the transgene phenotype exploited previous observations indicating that PTGS is associated with short 25-nucleotide RNA species, transgene methylation, and homology-dependent virus resistance. We also used the ability of turnip mosaic virus to suppress gene silencing as a means of dissecting stages of the mechanism. The results showed that a PVX:GFP amplicon induces weak PTGS and that this PTGS was enhanced in the presence of a GFP reporter gene. Our interpretation of these data is that the PTGS induced by the amplicon was genetically determined and equivalent to the initiation stage of the PTGS mechanism. The PTGS induced by the combined amplicon and reporter gene was equivalent to the maintenance stage and was associated with an epigenetic conversion of the transgene. The distinction between genetic and epigenetic PTGS explains the well-characterized effects of transgene dosage on PTGS that have been previously interpreted in terms of RNA expression thresholds.

Arabidopsis↗