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Biomedical subjects

D Gibson

Publications and source records attributed to D Gibson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Catalytically inactive protein phosphatase 2A can bind to polyomavirus middle tumor antigen and support complex formation with pp60(c-src).

Interaction between the heterodimeric form of protein phosphatase 2A (PP2A) and polyomavirus middle T antigen (MT) is required for the subsequent assembly of a transformation-competent MT complex. To investigate the role of PP2A catalytic activity in MT complex formation, we undertook a mutational analysis of the PP2A 36-kDa catalytic C subunit. Several residues likely to be involved in the dephosphorylation mechanism were identified and mutated. The resultant catalytically inactive C subunit mutants were then analyzed for their ability to associate with a cellular (B subunit) or a viral (MT) B-type subunit. Strikingly, while all of the inactive mutants were severely impaired in their interaction with B subunit, most of these mutants formed complexes with polyomavirus MT. These findings indicate a potential role for these catalytically important residues in complex formation with cellular B subunit, but not in complex formation with MT. Transformation-competent MT is known to associate with, and modulate the activity of, several cellular proteins, including pp60(c-src) family kinases. To determine whether association of MT with an active PP2A A-C heterodimer is necessary for subsequent association with pp60(c-src), catalytically inactive C subunits were examined for their ability to form complexes containing pp60(c-src) in MT-expressing cells. Two catalytically inactive C subunit mutants that efficiently formed complexes with MT also formed complexes that included an active pp60(c-src) kinase, demonstrating that PP2A activity is not essential in cis in MT complexes for subsequent pp60(c-src) association.

3T3 Cells↗
PubMed1999

Intravesical chemotherapy with epirubicin: a dose response study.

PURPOSE: We determined the difference in response to high and standard doses of intravesical epirubicin for treatment of superficial bladder cancer. MATERIALS AND METHODS: A total of 122 patients were entered into a randomized trial to compare the response of a marker tumor at 3 months, time to first recurrence and recurrence rates for 2 years after intravesical chemotherapy for superficial (pTa/pT1) bladder cancer. Patients were randomized to receive treatment for 1 hour with 1 (standard dose) or 2 mg./ml. (high dose) epirubicin (50 or 100 mg./50 ml. solution). RESULTS: There was no difference in the marker tumor response rate in 24 of 52 patients treated with the standard dose compared with 21 of 50 treated with the higher dose of epirubicin (p = 0.67). Similarly, the higher dose was not superior in regard to time to first recurrence, with a hazard ratio of 1.46 (p = 0.14, 95% confidence intervals 0.88 to 2.42). Considering the upper end of the confidence interval, we can reliably exclude an absolute difference of greater than 4% at 1 year for time to first recurrence in favor of higher dose chemotherapy. CONCLUSIONS: Epirubicin at double the standard dose for intravesical chemotherapy of superficial bladder cancer is not superior in regard to marker tumor response, time to first recurrence or recurrence rate.

Administration, Intravesical↗
PubMed1999

Strike contingency planning.

On Monday, February 26, 1996, the Ontario Public Service Employees Union (OPSEU) went on strike. The month-long strike included the 10 provincial psychiatric hospitals in Ontario. Within the psychiatric hospitals, the included direct care providers--RNs, RPNs, psychologists, social workers, occupational therapists--as well as support workers (food service, maintenance, housekeeping, and office employees). In anticipation, the mental health program at the London Health Science Centre (LHSC) developed a contingency plan that went into action when the strike was announced. This paper outlines the plan, describes what happened and makes recommendations for nurses who may be faced with similar situations.

Hospitals, General↗
PubMed1998

Monofunctional platinum amine complexes destabilize DNA significantly.

Both cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+ bind DNA covalently at the N7 site of guanine residues forming mono-dentate adducts. However, like cisplatin and transplatin, only the cis isomer has anti-cancer activity, whereas the trans-isomer does not. In order to understand the molecular basis of the different activities associated with cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+, the interactions of these two platinum compounds with the DNA heptamer CCTG*TCC:GGACAGG duplex (G* is the platinated guanine) have been examined. The reaction rate of cis-[Pt(NH3)2(4-Me-Py)Cl]+ with the single-stranded CCTGTCC is significantly faster than that of the trans isomer. The solution structure of the platinum-DNA adducts has been studied by two-dimensional NMR spectroscopy. Both the cis-platinum adducts and the trans-platinum adducts destabilize the DNA duplex significantly. The melting temperature (Tm) of the platinated heptamer duplex is estimated to be 10 degrees C lower than for the unplatinated duplex by NMR. At 2 degrees C, the base pairs located on the 5' side of the oligonucleotide, beyond the platinum lesion site, are disrupted. Over time, the platinum-DNA complex decomposes and the cis-[Pt(NH3)2(4-Me-Py)] platinum complex is gradually detached from DNA. No interstrand crosslinking is observed. The biological implications of the structural studies are discussed.

Amines↗
PubMed1998

Survey of the Administration of quality of life (QL) questionnaires in three multicentre randomised trials in cancer. The Medical Research Council Lung Cancer Working Party the CHART Steering Committee.

We surveyed centres collaborating in two trials in lung cancer (LU12, LU13) and one in lung and head and neck cancer (CHART) to find out how QL questionnaires were being administered, with the aim of standardising procedures and improving compliance. Dedicated local trials staff were funded for CHART but not for the other trials. In all three trials, patients completed a Rotterdam Symptom Checklist (RSCL) and a Hospital Anxiety and Depression Scale (HADS) at specified times. 17 of 22 LU12 centres, 9 of 11 LU13 and all 10 CHART centres returned survey forms. In LU12 and LU13, the category of staff responsible for questionnaires varied widely; in CHART, only research staff were involved. This led to more consistency in CHART centres in the administration and collection of questionnaires, and more frequent checking of forms. However, even the CHART administration, although better than in the other two trials, could not be regarded as standardised. All centres were equally affected by logistical problems. These embraced organisational deficits (e.g. unavailability of staff, lack of questionnaires) and patient-related factors (e.g. patient deemed to be too ill, had difficulty reading or left before completing the form). Patient refusals were an uncommon reason for non-compliance and patients were considered to be generally in favour of QL assessment. As a result of these findings, a number of measures have been put in place to increase standardisation of procedures and improve compliance. These include publishing guidelines for protocol writing, providing centres with guidelines for QL administration and information leaflets for patients, together with introducing staff training.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Ischemic stroke in a young patient with protein C deficiency and prothrombin gene mutation G20210A.

We report a patient who had an ischemic stroke aged 22 years, an inherited type I protein C deficiency and a heterozygous genotype of prothrombin gene 20210A. In view of recent reports of an increased risk for ischemic cerebral vascular disease in patients with the prothrombin 20210A mutation, we suggest that many of the reported cases of ischemic stroke and protein C deficiency may have had additional prothrombotic disorders such as the prothrombin mutation. The current data concerning the magnified risk for stroke in patients with the prothrombin 20210A mutation suggests the need to study all patients with premature stroke for this mutation and the other risk factors for thrombosis. This would include homocysteine, lupus inhibitor, anticardiolipin antibodies, and possibly the natural inhibitors of coagulation. It is possible that patients with the prothrombin 20210A mutation and ischemic cerebral vascular disease would benefit from long-term anticoagulation therapy in a similar way to patients with the antiphospholipid syndrome.

Adult↗
PubMed1998

Self-reported sleep and mood disturbance in chronic pain patients.

OBJECTIVE: To evaluate the prevalence of self-reported sleep disturbance and its relationship to mood disturbance in chronic pain patients. DESIGN AND SETTING: Survey of patients referred to a multidisciplinary outpatient pain clinic. PATIENTS: The sample consisted of 105 consecutive patients (59 men and 46 women), with an average age of 41.5 (SD +/-13.4) years. MEASURES: Self-report measures of sleep disturbance and visual analog scales of mood disturbance (anxiety and depression) and pain experience (intensity and unpleasantness). RESULTS: Patients were grouped according to whether they considered themselves "poor" (n = 68) or "good" (n = 37) sleepers. Poor sleepers reported more difficulties initiating and maintaining sleep and greater pain intensity and pain unpleasantness than did good sleepers. The two groups did not differ on measures of depressive or anxious mood. CONCLUSION: The results suggest that sleep disturbance is a prevalent complaint in chronic pain patients, but it is not always associated with an underlying mood disturbance.

Adult↗
PubMed1997

Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee.

BACKGROUND: Human tumour cells can proliferate rapidly, and giving radiotherapy in many small fractions may reduce long-term normal-tissue morbidity. In response to these observations, we developed the CHART (continuous hyperfractionated accelerated radiotherapy) regimen, which uses thirty-six small fractions of 1.5 Gy given three times per day, to give 54 Gy in only 12 consecutive days. We report the long-term follow-up of a trial of CHART versus conventional radiotherapy in patients with locally advanced non-small-cell lung cancer (NSCLC). METHODS: 563 patients were entered by thirteen centres between April, 1990, and March, 1995. We included patients with NSCLC localised to the chest with a performance status of 0 or 1 in whom radical radiotherapy was chosen as the definitive management. Patients were randomly allocated in a 3:2 ratio to CHART or conventional radiotherapy. The latter was thirty fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. RESULTS: The groups were well matched for possible prognostic factors. Overall there was a 24% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2-year survival of 9% from 20% to 29% (p = 0.004, 95% CI 0.63-0.92). Subgroup analyses (predefined) suggest that the largest benefit occurred in patients with squamous cell carcinomas (82% of the cases), in whom there was a 34% reduction in the relative risk of death (an absolute improvement at 2 years of 14% from 19% to 33%). During the first 3 months, severe dysphagia occurred more often in the CHART group than in the group on conventional radiotherapy (19 vs 3%). Otherwise, there were no important differences in short-term or long-term morbidity. INTERPRETATION: CHART compared with conventional radiotherapy gave a significant improvement in survival of patients with NSCLC. Further improvement may be achieved with dose escalation in conformal radiotherapy, by the addition of cytotoxic chemotherapy, and by hypoxic cell radiosensitisation.

Adult↗
PubMed1997

A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer.

BACKGROUND AND PURPOSE: Continuous, hyperfractionated, accelerated radiotherapy (CHART) has shown promise of improved tumour control and reduced late morbidity in pilot studies and has now been tested in a multicentre randomised controlled clinical trial. MATERIAL AND METHODS: Patients with squamous cell cancer in the main sites within the head and neck region with the general exception of early T1 N0 tumours were entered into the study by 11 centres. There was a 3:2 randomisation to either CHART, where a dose of 54 Gy was given in 36 fractions over 12 days, or to conventional therapy where 66 Gy was given in 33 fractions over 6.5 weeks. A total of 918 patients were included over a 5 year period from March 1990. RESULTS: ACUTE MORBIDITY: Acute radiation mucositis was more severe with CHART, occurred earlier but settled sooner and was in nearly all cases healed by 8 weeks in both arms. Skin reactions were less severe and settled more quickly in the CHART treated patients. TUMOUR CONTROL AND SURVIVAL: Life table analyses of loco-regional control, primary tumour control, nodal control, disease-free interval, freedom from metastasis and survival showed no evidence of differences between the two arms. In exploratory subgroup analyses there was evidence of a greater response to CHART in younger patients (P = 0.041) and poorly differentiated tumours appeared to fare better with conventional radiotherapy (P = 0.030). In the larynx there was evidence of a trend towards increasing benefit with more advanced T stage (P = 0.002). LATE TREATMENT RELATED MORBIDITY: Osteoradionecrosis occurred in 0.4% of patients after CHART and 1.4% of patients after conventional radiotherapy. The incidence of chondritis or cartilage necrosis was similar in both arms. Life table analysis showed evidence of reduced severity in a number of late morbidities in favour of CHART. These were most striking for skin telangiectasia, superficial and deep ulceration of the mucosa and laryngeal oedema. CONCLUSION: Similar local turnout control was achieved by CHART as compared with conventional radiotherapy despite the reduction in total dose from 66 to 54 Gy supporting the importance of repopulation as a cause of radiation failure. The effects seen in advanced laryngeal cancer and those related to histological differentiation need further study. Reduced late morbidity is a factor which together with patient preference should be considered in the decision as to the programme of radiotherapy to employ in the curative treatment of head and neck cancer.

Adult↗
PubMed1997

Impaired recognition of disgust in Huntington's disease gene carriers.

Face processing and facial expression recognition were investigated in the earliest stages of Huntington's disease, by studying 40 people who presented for genetic testing. Twenty-three of these 'at risk' individuals turned out not to carry the gene for Huntington's disease (the AR- group). Seventeen were found to be gene carriers (the AR+ group); 15 from genetic testing, and two who showed signs of early stages of Huntington's disease. A number of standard tasks were used to provide background information, including recognition memory for words, picture naming, verbal fluency, and figure copying; none revealed significant differences between the AR+ and AR- groups. Face processing abilities were investigated using tests of identification of familiar (famous) faces, unfamiliar face matching, recognition memory for faces, and recognition of facial expressions of emotion. No statistically significant differences between the AR+ and AR- groups were found for any of these tests, but the AR+ group showed a borderline overall impairment in recognizing facial expressions of emotion (0.05 < P < 0.1). When recognition of each of the six basic emotions used was examined separately, only disgust was found to be significantly impaired. This highly selective deficit in the recognition of disgust was confirmed in the subgroup of 15 individuals shown by genetic testing to be Huntington's gene carriers; it was therefore found in people who were free from clinical symptoms and did not perform significantly more poorly than non-carriers on any of the background tests, on any of the other face processing tasks, and even for recognition of any other basic emotion. This points strongly to the importance of the basal ganglia in the emotion of disgust.

Adult↗
PubMed1996

The cytosolic pathway of L-malic acid synthesis in Saccharomyces cerevisiae: the role of fumarase.

Saccharomyces cerevisiae accumulates L-malic acid but not only minute amounts of fumaric acid. A 13C-nuclear magnetic resonance study following the label from glucose to L-malic acid indicates that the L-malic acid is synthesized from pyruvic acid via oxaloacetic acid. From this, and from previously published studies, we conclude that a cytosolic reductive pathway leading from pyruvic acid via oxaloacetic acid to L-malic acid is responsible for the L-malic acid production in yeast. The non-production of fumaric acid can be explained by the conclusion that, in the cell, cytosolic fumarase catalyzes the conversion of fumaric acid to L-malic but not the reverse. This conclusion is based on the following findings. (a) The cytosolic enzyme exhibits a 17-fold higher affinity towards fumaric acid than towards L-malic acid; the Km for L-malic acid is very high indicating that L-malic acid is not an in vivo substrate of the enzyme. (b) Overexpression of cytosolic fumarase does not cause accumulation of fumaric acid (but rather more L-malic acid). (c) According to 13C NMR studies there is no interconversion of cytosolic L-malic and fumaric acids.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed1996

The application of local grey level histograms to organelle classification in histological images.

The performance of a histogram matching algorithm was evaluated for the classification of organelles in histological images. The test set used for this investigation comprised several digital images of sheep pituitary gland captured using a CCD camera linked to a Tunnelling Electron Microscope. Results show that the normalized image histogram is a good feature to choose as the basis of object recognition in biological images.

Algorithms↗
PubMed1996

Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee.

While radiotherapy is proceeding, tumour cells may proliferate. The use of small individual doses reduces late morbidity. Continuous hyperfractionated accelerated radiation therapy (CHART), which reduces overall treatment from 6-7 weeks to 12 days and gives 36 small fractions, has now been tested in multicentre randomised controlled clinical trials. The trial in non-small-cell lung cancer included 563 patients and showed improvement in survival; 30% of the CHART patients were alive at 2 years compared with 20% in the control group (P = 0.006). In the 918 head and neck cases, there was only a small, non-significant improvement in the disease-free interval. In this interim analysis there was a trend for those with more advanced disease (T3 and T4) to show advantage; this will be subject to further analysis when the data are more mature. The early mucosal reactions appeared sooner and were more troublesome with CHART, however they quickly settled; so far no difference in long-term morbidity has emerged. These results support the hypothesis that tumour cell repopulation can occur during a conventional course of radiotherapy and be a cause of treatment failure.

Adult↗