Biomedical subjects

P Ross

Publications and source records attributed to P Ross.

At least 37 records · Page 2Linked to original sources

PubMed2000

Gene therapy: recent progress in the clinical oncology arena.

Despite the rapid technological advances that continue to sustain the field of cancer gene therapy, few individual patients have benefited from the revolution so far. The plethora of clinical trials described confirms that each malignancy will have its own ideal strategy based on the associated molecular defects, and there has been rapid progress from this viewpoint. At the same time, there has been a renewed appreciation for the limitations to gene therapy, which include low efficiency of gene transfer, poor specificity of response and methods to accurately evaluate responses, and lack of truly tumor-specific targets at which to aim. As with all new therapies, we are climbing a steep learning curve in terms encountering treatment-related toxicities, as well as profound ethical and regulatory issues.

Animals↗

PubMed1999

Cloning and localization of Rab3 isoforms in bovine, rat, and human parathyroid glands.

Rab3 proteins are small GTP-binding proteins known to play a role in regulated exocytosis processes. This study examines the expression of Rab3 mRNA and protein in bovine, rat and human parathyroid glands. mRNAs of several Rab3 isoforms were detected in bovine (Rab3A, Rab3B and Rab3C) and rat (Rab3A, Rab3B and Rab3D) parathyroid glands by RT-PCR and sequencing. Rab3A protein was detected in the cytosolic extract from bovine parathyroid gland by Western blotting using a monoclonal antibody for Rab3A. Rab3A protein was localized to parathyroid hormone-containing chief cells by immunohistochemical staining. Subcellular localization of Rab3A protein by immunogold electron microscopy revealed that the majority of Rab3A protein was not associated with dense-core vesicles, but localized in the cytosol of the chief cells. Altogether, our results demonstrate that Rab3 isoforms are expressed in parathyroid chief cells, suggesting that they may play a role in regulated exocytosis in these cells.

Animals↗

PubMed1999

Improving electrotransfection efficiency by post-pulse centrifugation.

We have demonstrated that the viability of electrotransfected adherent CHO and suspended NK-L, K-562, L1210 and MC2 cells is improved if pelleting by centrifugation is performed immediately after pulsing. The protection effect on cell viability is cell line- and pellet thickness-dependent. For forming CHO cell pellets, centrifugation force (300-13,000 g) and duration are not crucial; about five to 10 cell layers in the pellet provide the optimal protection effect. NK-L, K-562, L1210 and MC2 cell pellets are optimally formed by centrifugation at 13,000 g in an Eppendorf desktop centrifuge. Pelleting improves the cell viability over the whole range of the NK-L, K-562, L1210 and MC2 cell concentrations studied. When this pelleting method is applied to load CHO cells with FITC-dextran (41,000 MW), not only is the success rate close to 100%, but the growth rate is similar to the control, which is far better than the conventional electroporation method. Furthermore, the transfection efficiency of the five cell lines in pellet is significantly higher than that in suspension.

Animals↗

PubMed1999

The study of the process of fluid-phase endocytosis in cervical squamous cells using fluorescent microspheres.

Physiological processes in cervical squamous epithelium have not been extensively studied. Perhaps understandably, most of the research has concentrated on the pathology of the cervix, in particular dysplasia and malignancy. Fluid-phase endocytosis is a physiological process which has been demonstrated to be important in understanding disease development at other squamous epithelial sites, e.g. oesophagus. In this study, we have demonstrated by a new methodology developed in our laboratory using fluorescent microspheres and flow cytometry that fluid-phase endocytosis occurs in cervical squamous cells. The process has been shown to be dose- and time-dependent. This novel approach provides a means to improve our understanding of the physiological functions of the cervix and may provide insight into the pathogenesis of cervical neoplastic and non-neoplastic disease.

Cervix Uteri↗

PubMed1998

Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group.

BACKGROUND: Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption, but the balance between its long-term risks and benefits remains unclear. Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear. METHODS: We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age. An additional 435 women who were prepared to receive a combination of estrogen and progestin were randomly assigned to one of the above treatments or open-label estrogen-progestin. The main outcome measure was the change in bone mineral density of the lumbar spine, hip, distal forearm, and total body measured annually for two years by dual-energy x-ray absorptiometry. RESULTS: The women who received placebo lost bone mineral density at all measured sites, whereas the women treated with 5 mg of alendronate daily had a mean (+/-SE) increase in bone mineral density of 3.5+/-0.2 percent at the lumbar spine, 1.9+/-0.1 percent at the hip, and 0.7+/-0.1 percent for the total body (all P<0.001). Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density. Alendronate did not increase bone mineral density of the forearm, but it slowed the loss. The responses to estrogen-progestin were 1 to 2 percentage points greater than those to the 5-mg dose of alendronate. Alendronate was well tolerated, with a safety profile similar to that of placebo or estrogen-progestin. CONCLUSIONS: Alendronate prevents bone loss in postmenopausal women under 60 years of age to nearly the same extent as estrogen-progestin.

Alendronate↗

PubMed1998

Clinical report on long-term bone density after short-term EMF application.

A 1984 study determined the effect of a 72 Hz pulsating electromagnetic field (PEMF) on bone density of the radii of post-menopausal (osteoporosis-prone) women, during and after treatment of 10 h daily for 12 weeks. Bone mineral densities of the treated radii increased significantly in the immediate area of the field during the exposure period and decreased during the following 36 weeks. Bone density determination of the radii of these women, remeasured after eight years, suggests no long-term changes. The bone density-enhancing effect of PEMFs should be further studied, alone and in combination with exercise and pharmacologic agents such as the bisphosphonates and hormones, as prophylaxis in the osteoporosis-prone postmenopausal woman and as a possible block to the demineralization effect of microgravity.

Absorptiometry, Photon↗

PubMed1998

Correlation of CT with histopathological findings in patients with gastric and gastro-oesophageal carcinomas following neoadjuvant chemotherapy.

UNLABELLED: Gastric carcinoma is the fourth commonest cause of death from malignant disease in United Kingdom. In the Western hemisphere, it usually presents with advanced disease, which contributes to its very poor prognosis. Pre-operative (neoadjuvant) chemotherapy offers the possibility of down-staging such tumours and the potential to render tumours operable. Computed tomography (CT) plays a central role in the assessment of patients presenting with the disease, and in those who undergo chemotherapy, in evaluating their response. OBJECTIVE: This study was undertaken to evaluate the role of CT in predicting loco-regional spread of tumour following neoadjuvant chemotherapy in non-metastatic gastric and gastro-oesophageal cancers. METHODS AND MATERIALS: We correlated CT evidence of loco-regional spread with pathological findings following surgery in 21 patients who received pre-operative chemotherapy. RESULTS: Residual masses were seen on CT in 19 patients, and 15 contained active tumour, although in four patients no viable tumour was demonstrated at histopathology. The overall accuracy of CT in assessing loco-regional disease was disappointing with sensitivities, specificities, positive and negative predictive values of 57%, 43%, 75% and 33%, respectively. CONCLUSIONS: We conclude that CT is not accurate in identifying residual loco-regional spread and therefore should not preclude surgery in those patients who have received neoadjuvant chemotherapy.

Adult↗

PubMed1998

High level multiplex genotyping by MALDI-TOF mass spectrometry.

A primer extension assay is used to perform highly multiplexed genotyping of single nucleotide polymorphisms (SNPs) present in genomic DNA amplified by a multiplex PCR. The assay uses matrix-assisted laser desorption ionization time-of-flight mass spectrometry to accurately measure the masses of short oligonucleotide primers extended by a single dideoxynucleotide. The multiplexed genotyping assays rely on the natural molecular weight differences of DNA bases. By careful analysis of primer composition complementary to the target, or by judicious addition of one or more noncomplementary 5' bases to the genotyping primers, mass spectra of interleaved genotyping products can be generated with no ambiguity in allele assignment. Using a model multiplex PCR system, we demonstrate the ability to perform 12-fold multiplex SNP analysis.

Base Sequence↗

PubMed1998

The Royal Marsden experience of a small bowel adenocarcinoma treated with protracted venous infusion 5-fluorouracil.

The purpose of this study was to review the efficacy of a protracted venous infusion of 5-fluorouracil (PVI 5-FU)-based chemotherapy in advanced small bowel adenocarcinoma. Data on all patients with small bowel malignancy who were seen at a single institution over a 5-year period were retrieved from the gastrointestinal unit and hospital databases, and these cases were reviewed. Eight patients with advanced small bowel adenocarcinoma received PVI 5FU-based chemotherapy. The overall response rate in assessable patients was 37.5% (3/8). The median overall survival was 13 months (range 1-28), and progression-free survival was 7.8 months (range 0-15). Overall, the treatment was well tolerated and symptomatic benefit was seen. In conclusion, PVI 5-FU has activity in this disease. This should be assessed either as a single agent or as part of a combination regimen such as epirubicin/cisplatin/PVI FU (ECF) in a multicentre randomized study.

Adenocarcinoma↗

PubMed1998

Adiposity and blood pressure in a multiethnic population of women in Hawaii.

OBJECTIVE: To compare the amount and distribution of fat among White, Japanese, Filipino and Hawaiian women and to investigate associations between measures of adiposity and serum cholesterol and blood pressure. DESIGN: Cross-sectional survey of adiposity, serum cholesterol and blood pressure of 421 volunteer women of White (N = 137), Japanese (N = 144), Filipino (N = 74) and Hawaiian (N = 66) ethnicities, age 25-35 years. Anthropometric measures (weight; height; subscapular, bicep, tricep, suprailiac and calf skinfold thickness; waist, hip and mid-upper arm circumferences), grip strength, serum cholesterol and blood pressure. RESULTS: Hawaiian women had the highest levels of adiposity by all measures. Asian women (especially Filipinos) had higher subscapular skinfold thicknesses than did Whites and, for the same value of body mass index (BMI), had a greater percentage of body fat. BMI was the strongest correlate of systolic blood pressure, while subscapular skinfold thickness was the strongest correlate of diastolic blood pressure. Blood pressure varied by adiposity but not ethnicity. No measures of body fat were associated with serum cholesterol. CONCLUSION: Higher body fat measures, especially BMI, were associated with higher systolic blood pressure. However, higher subscapular skinfold (upper body) thickness was also associated with higher diastolic blood pressure. Subscapular fatness appears to be especially important among women of Asian ethnicity, Filipino women in particular.

Adult↗

PubMed1998

Three cdg operons control cellular turnover of cyclic di-GMP in Acetobacter xylinum: genetic organization and occurrence of conserved domains in isoenzymes.

Cyclic di-GMP (c-di-GMP) is the specific nucleotide regulator of beta-1,4-glucan (cellulose) synthase in Acetobacter xylinum. The enzymes controlling turnover of c-di-GMP are diguanylate cyclase (DGC), which catalyzes its formation, and phosphodiesterase A (PDEA), which catalyzes its degradation. Following biochemical purification of DGC and PDEA, genes encoding isoforms of these enzymes have been isolated and found to be located on three distinct yet highly homologous operons for cyclic diguanylate, cdg1, cdg2, and cdg3. Within each cdg operon, a pdeA gene lies upstream of a dgc gene. cdg1 contains two additional flanking genes, cdg1a and cdg1d. cdg1a encodes a putative transcriptional activator, similar to AadR of Rhodopseudomonas palustris and FixK proteins of rhizobia. The deduced DGC and PDEA proteins have an identical motif structure of two lengthy domains in their C-terminal regions. These domains are also present in numerous bacterial proteins of undefined function. The N termini of the DGC and PDEA deduced proteins contain putative oxygen-sensing domains, based on similarity to domains on bacterial NifL and FixL proteins, respectively. Genetic disruption analyses demonstrated a physiological hierarchy among the cdg operons, such that cdg1 contributes 80% of cellular DGC and PDEA activities and cdg2 and cdg3 contribute 15 and 5%, respectively. Disruption of dgc genes markedly reduced in vivo cellulose production, demonstrating that c-di-GMP controls this process.

Amino Acid Sequence↗

PubMed1998

Effects of hypoproteinemia-induced myocardial edema on left ventricular function.

In previous studies, we observed left ventricular (LV) systolic and diastolic dysfunction in association with interstitial myocardial edema (IME) induced by either coronary venous hypertension (CVH) or lymphatic obstruction. In the present study, we examined the effects of myocardial edema induced by acute hypoproteinemia (HP) on LV systolic and diastolic function. We also combined the methods of HP and CVH (HP-CVH) to determine their combined effects on LV function and myocardial water content (MWC). We used a cell-saving device to lower plasma protein concentration in HP and HP-CVH groups. CVH was induced by inflating the balloon in the coronary sinus. Six control dogs were treated to sham HP. Conductance and micromanometer catheters were used to assess LV function. Contractility, as measured by preload recruitable stroke work, did not change in control or HP groups but declined significantly (14.5%) in the HP-CVH group. The time constant of isovolumic LV pressure decline (tau) increased significantly from baseline by 3 h in the HP (24.8%) and HP-CVH (27.1%) groups. The end-diastolic pressure-volume relationship (stiffness) also increased significantly from baseline by 3 h in the HP (78.6%) and HP-CVH (42.6%) groups. Total plasma protein concentration decreased from 5.2 +/- 0.2 g/dl at baseline to 2.5 +/- 0.0 g/dl by 3 h in the HP and HP-CVH groups. MWC of the HP (79.8 +/- 0.25%) and HP-CVH groups (79.8 +/- 0.2%) were significantly greater than that of the control group (77.8 +/- 0.3%) but not different from one another. In conclusion, hypoproteinemia-induced myocardial edema was associated with diastolic LV dysfunction but not systolic dysfunction. The edema caused by hypoproteinemia was more than twice that produced by our previous models, yet it was not associated with systolic dysfunction. CVH had a negative inotropic effect and no significant influence on MWC. IME may not have the inverse causal relationship with LV contractility that has been previously postulated but appears to have a direct causal association with diastolic stiffness as has been previously demonstrated.

Acid-Base Equilibrium↗

PubMed1998

Solving a real-world problem using an evolving heuristically driven schedule builder.

This work addresses the real-life scheduling problem of a Scottish company that must produce daily schedules for the catching and transportation of large numbers of live chickens. The problem is complex and highly constrained. We show that it can be successfully solved by division into two subproblems and solving each using a separate genetic algorithm (GA). We address the problem of whether this produces locally optimal solutions and how to overcome this. We extend the traditional approach of evolving a "permutation + schedule builder" by concentrating on evolving the schedule builder itself. This results in a unique schedule builder being built for each daily scheduling problem, each individually tailored to deal with the particular features of that problem. This results in a robust, fast, and flexible system that can cope with most of the circumstances imaginable at the factory. We also compare the performance of a GA approach to several other evolutionary methods and show that population-based methods are superior to both hill-climbing and simulated annealing in the quality of solutions produced. Population-based methods also have the distinct advantage of producing multiple, equally fit solutions, which is of particular importance when considering the practical aspects of the problem.

Algorithms↗

PubMed1998

Adapting operator settings in genetic algorithms.

In the majority of genetic algorithm implementations, the operator settings are fixed throughout a given run. However, it has been argued that these settings should vary over the course of a genetic algorithm run--so as to account for changes in the ability of the operators to produce children of increased fitness. This paper describes an investigation into this question. The effect upon genetic algorithm performance of two adaptation methods upon both well-studied theoretical problems and a hard problem from operations research, the flowshop sequencing problem, are therefore examined. The results obtained indicate that the applicability of operator adaptation is dependent upon three basic assumptions being satisfied by the problem being tackled.

Algorithms↗

PubMed1998

Labetalol does not lengthen asystole during electroconvulsive therapy.

Labetalol, a combined alpha- and beta-adrenergic blocker is often used to attenuate the transient increases in heart rate and blood pressure that accompany electroconvulsive therapy (ECT). It has been suggested that labetalol should not be administered during ECT without the protection provided by anticholinergic medications, because of its potential severe bradycardic effects. We present our experience with 32 patients from all age groups who received labetalol without anticholinergic treatment during ECT. None of the patients demonstrated adverse bradycardic effects. We conclude that administration of labetalol during ECT does not routinely require premedication with anticholinergic drugs and does not lengthen asystole.

Adrenergic alpha-Agonists↗

PubMed1997

BCL-2 antisense therapy in patients with non-Hodgkin lymphoma.

BACKGROUND: Overexpression of BCL-2 is common in non-Hodgkin lymphoma and leads to resistance to programmed cell death (apoptosis) and promotes tumorigenesis. Antisense oligonucleotides targeted at the open reading frame of the BCL-2 mRNA cause a specific down-regulation of BCL-2 expression which leads to increased apoptosis. Lymphoma grown in laboratory animals responds to BCL-2 antisense oligonucleotides with few toxic effects. We report the first study of BCL-2 antisense therapy in human beings. METHODS: A daily subcutaneous infusion of 18-base, fully phosporothioated antisense oligonucleotide was administered for 2 weeks to nine patients who had BCL-2-positive relapsed non-Hodgkin lymphoma. Toxicity was scored by the common toxicity criteria, and tumour response was assessed by computed tomography scan. Efficacy was also assessed by quantification of BCL-2 expression; BCL-2 protein levels were measured by flow cytometry in samples from patients. FINDINGS: During the course of the study, the daily dose of BCL-2 antisense was increased incrementally from 4.6 mg/m2 to 73.6 mg/m2. No treatment-related toxic effects occurred, apart from local inflammation at the infusion site. In two patients, computed tomography scans showed a reduction in tumour size (one minor, one complete response). In two patients, the number of circulating lymphoma cells decreased during treatment. In four patients, serum concentrations of lactate dehydrogenase fell, and in two of these patients symptoms improved. We were able to measure BCL-2 levels by flow cytometry in the samples of five patients, two of whom had reduced levels of BCL-2 protein. INTERPRETATION: In patients with relapsing non-Hodgkin lymphoma, BCL-2 antisense therapy led to an improvement in symptoms, objective biochemical and radiological evidence of tumour response, and down-regulation of the BCL-2 protein in some patients. Our findings are encouraging and warrant further investigations of BCL-2 antisense therapy in cancer treatment.

Adult↗

PubMed1997

Performance of the new plasma-compatible Advantage blood glucose test strips.

OBJECTIVE: To establish a plasma calibration curve for the Advantage Blood Glucose System that would permit direct comparison with results provided by clinical laboratories. DESIGN AND METHODS: The initial study involved the comparison between the Advantage whole blood referenced results and the laboratory plasma results. The second study validated the plasma-compatibility of the first new lot of Advantage test strips with this new calibration curve. RESULTS: Plasma and whole blood glucose data, obtained at Hôpital Maisonneuve-Rosemont in Montréal, demonstrated the typical differences between these two sample types. Mathematical correction of the Advantage results eliminated this difference. This new equation was then encoded into the code keys of a new lot of Advantage test strips and a second study was conducted to verify the comparability to laboratory plasma glucose. CONCLUSION: The results for the Advantage Blood Glucose System may now be compared directly with the laboratory plasma or serum glucose results.

Blood Chemical Analysis↗

PubMed1997

A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer.

BACKGROUND: To compare protracted venous infusion (PVI) 5-fluorouracil (5-FU) with and without mitomycin C (MMC) in a prospectively randomised study and analyse for tumour response, survival, toxicity and quality of life (QL). PATIENTS AND METHODS: Two hundred patients with advanced colorectal cancer received PVI 5-FU 300 mg/m2/day for a maximum of 24 weeks and were randomised to PVI 5-FU alone or PVI 5-FU + MMC 10 mg/m2 (7 mg/m2 from June 1995) 6 weekly for 4 courses. RESULTS: Overall response was 54% (95% confidence interval [CI] 44.1%-63.9%) with PVI 5-FU + MMC compared to 38% (95% CI: 28.3%-47.7%) for PVI 5-FU alone (P = 0.024). The median failure free survival was 7.9 months in PVI 5-FU plus MMC and 5.4 months with PVI 5-FU alone (P = 0.033) and at one year 31.9% for the combination compared to 17.7% for PVI 5-FU alone. Median survival was 14 months with MMC and 15 months in 5-FU alone; one-year survival 51.7% vs. 57.2%. PVI 5-FU + MMC caused more overall haematological toxicity but CTC grades 3/4 was increased only for thrombocytopaenia. Two patients treated with a cumulative dose of MMC of 40 mg/m2 developed haemolytic uraemic syndrome warranting the reduction in cumulative MMC dose to 28 mg/m2. The global QL scores were better for PVI 5-FU + MMC arm at 24 weeks, but the remaining QL data showed no differences. CONCLUSIONS: PVI 5-FU + MMC results in failure-free survival and response advantage, tolerable toxicity and better QL when compared to PVI 5-FU alone but no overall survival advantage. There is no irreversible toxicity with MMC at a cumulative dose of 28 mg/m2.

Adenocarcinoma↗